Skip to main content
Download PDF

Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview

Cancer Cell International volume 22, Article number: 246 (2022) Cite this article

Abstract

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

Introduction

Cancer is the abnormal and anarchic development of cells, with the potential to invade or spread to various parts of the body [1, 2]. Cancer can occur in any part of the body, and cancer cells can invade other organs in different ways (neighbourhood invasion, hematogenous or lymphatic) [3,4,5]. In 2020, there have been an estimated 18.1 million cancer cases worldwide. Men accounted for 9.3 million of the cases, while women accounted for 8.8 million. Because of recent advances in novel therapeutics, the diagnosis rate has been increasing in recent years, which has improved the general life expectancy for patients [6, 7]. Each cancer type can be subdivided now based on mutations of several genes with the aid of advances in molecular diagnostics [8,9,10], indicative of the molecular patterns that are malfunctioning. Consequently, this allows effective intervention with tailored treatments by blocking certain biological processes of tumor cells which allows effective interference with targeted therapeutics by impeding specific biological pathways of tumor-infected cells [9, 11]. Cancer is frequently associated with the number of mutations that interrupt the key signaling pathways [12,13,14]. Cellular signaling pathways are organized as modular networks that communicate in real-time [15, 16]. Pathway components work together in a switch-like fashion, with interactions between two proteins that result in either indirect or direct inhibition or activation of the next factor [17,18,19,20]. The pathogenesis of numerous signaling pathways is maintained by transcriptomic, epigenetic, and genetic changes [21, 22].

Nowadays, molecular diagnostic tools became more widely available in clinical settings and that help identifies specific mutational patterns of cancer [23, 24]. Subsequently, this condition becomes an effective method for identifying patients with similar alterations, which was used to determine effective treatment modules [22, 25, 26]. Despite this progress, resistance to cancer therapy remains the main issue i.e., common side effects in patients who have received first-line treatment. Targeted therapy, which employs a variety of small molecules that play a role as inhibitors for the key signaling stages, can result in resistance in a few instances even from first doses. Resistance develops as a consequence of tumor cells being positively designated for mechanisms that can compensate for the specifically targeted pathway [18, 27, 28].

Cancer cells have a low dependence on external proliferative stimuli and often do not need such stimulation to multiply; through the mutations of some oncogenes, these cells acquire a proliferative autonomy, producing their mitogenic signals [29]. One of the key characteristics of cancer cells is probably their ability to permanently stimulate their growth and proliferation [30]z. To understand this property, it is useful to remember that normal cells need the growth and division of external mitogenic signals (mainly represented by growth factors), produced (in a diffusible form) by other cells (paracrine signaling). These molecules (ligands) bind to specific transmembrane receptors, which, after activation, transmit the signal—through branched intracellular signaling pathways—to the nucleus, triggering division. The whole process is regulated by negative feedback mechanisms, which attenuate excessive proliferative signaling (make it transient) and, if it persists, induce cell senescence and apoptosis [31].

Cancer cells have a low dependence on external proliferative stimuli and often do not need such stimulation to multiply; through the mutations of some oncogenes, these cells acquire a proliferative autonomy, producing their mitogenic signals [24, 32]. The major strategies used by tumor cells to achieve proliferative independence are as follows:

  • Production of their growth factors, to which they respond by proliferation (autocrine signaling) (for example, TGF-α in sarcomas) [33]

  • Disorder of growth factor receptors, which transduce proliferative signals inside the cell; Disorder involves either overexpression of receptors in many cancers (e.g., amplification of the HER2/neu receptor in about 30% of breast cancers or EGFR in non-small cell lung cancer) or alteration of their structure, which results in receptor activation and therefore signaling, without ligand (for example, truncated version of EGF receptor) [34].

  • Alteration of the components of cytoplasmic signaling pathways, which produce a flow of mitogenic signaling without their stimulation by receptors; for example, the mitogen-activated protein kinase pathway, which consists of RAS → RAF → MEK → MAPK → ERK → FOS proteins, plays a central role in about 25% of human cancers [35].

In addition to their ability to intensely stimulate their growth and proliferation (by activating oncogenes), cancer cells are insensitive to signals that could stop cell division. In normal tissues, multiple antiproliferative signals act, external or internal, which maintain tissue homeostasis [36]. Exogenous inhibitory signals—either soluble (TGF-β) or embedded in the extracellular matrix and the surface of neighbouring cells (by cadherin-like adhesion molecules, which cause “contact inhibition”) 2—are received by transmembrane receptors coupled with intracytoplasmic circuits. signaling, which blocks cell division. Cells move from the postmitotic G1 stage to the resting G0 phase, from where they can return to the cell cycle—when conditions allow—or permanently give up division and differentiate into specific cells [37].

Complex like MAPK is one compound that linked signaling cascade with frequent participation in tumor development, oncogenesis, and resistance of the drug [38, 39]. The MAPK family includes a large number of kinases that are altered in cancer and for which several targeted therapies have been developed [40]. Resistance to MAPK inhibitors is a current issue, owing to the high degree of interactions and perhaps compensating responses. Thus, in this review, we look at the many repercussions of MAPK pathways in cancer, with a specific emphasis on tumor signaling regulation via MAPK interaction with critical signaling pathways in pathological situations [8]. The current review will concentrate particularly on the pathways of the canonical primary signal transduction depicted in Fig. 1.

Fig. 1
figure 1

Diagram with involved canonical ERK pathways in primary signal transduction and their associated cellular processes

Full size image

Review methodology

This review has been based on the use of several databases such as PubMed/Medline, Web of Science, TRIP Database, and Up-to-Date using for searching the next MeSH terms: “Antineoplastic Agents/pharmacology”, “Biological Products/chemistry”, “Biological Products/therapeutic use”, “Cell Line”, “MAP Kinase Signaling System/drug effects”, “Extracellular Signal-Regulated MAP Kinases/metabolism”, “Mitogen-Activated Protein Kinase Kinases/antagonists and inhibitors”, “Mitogen-Activated Protein Kinase Kinases/metabolism”, “Neoplasms/drug therapy”, “Neoplasms/metabolism”, “Neoplasms/pathology”, “Plants/chemistry”, “Proto-Oncogene Proteins p21(Ras)”, “Signal Transduction/drug effects”, “Ras Proteins/antagonists and inhibitors”, “Ras Proteins/genetics”, “Ras Proteins/metabolism”, “Xenograft Model Antitumor Assays”.

The study included papers published in English that contained molecular pharmacological data on the anticancer action of the phytochemicals mentioned in our study, studies with broad therapeutic perspectives of application, and studies with a high rate of citations. Studies published in languages other than English, studies without obvious pharmacological mechanisms, and studies that included homeoopathic preparations as complementary treatment were excluded.

Ras-ERK and natural bioactive compounds in chemotherapy and chemoprevention: structure—activity relationship and experimental evidence

Phytochemicals and similar derivative compounds have been shown to play an essential role as cancer treatment agents [2, 41,42,43]. The majority of protein kinase inhibitors found in plants are flavonoids, which are polyketides. Anthraquinones and anthrones, which contain representatives such as hypericin and emodin, are also part of this chemical group. Both compounds have been shown to inhibit protein kinases like CK2 and p65lck [44]. With alkaloids, most of the flavonoid group are valuable “folk medicine” effective for a variety of ailments other than cancer. However, even when proved to be beneficial in the treatment of cancer, various mechanisms other than intervening with protein kinases have been reported [45, 46].

The extracts of wine polyphenol inhibit the cell cycle progression, cause apoptosis via the caspase activation, and alter the activity of the metalloproteinase (MMP) enzyme. Resveratrol, which is stilbene present in lots of foods including red wine grapes, is thought to provide several health advantages. Protein kinases including MEK/ERK1/2, AKT, RAF, JNK and CamKK, have been demonstrated to be inhibited by it. As a result, it is tempting to infer that the reported “anticancer effects” are due to interfering with the different protein kinases. However, considering the modest levels of resveratrol absorbed by wine intake, this may be more apparent than genuine. Even consuming the ultra-pure resveratrol component should not be enough to have a discernible influence on the activity of cellular protein kinase. Furthermore, considering the relatively high number of distinct protein kinases that are affected by resveratrol, it is impossible to rule out unfavourable side effects when significant doses are used.

A similar argument may be made for the other natural chemicals discussed in this review. An example: secondary metabolites include alkaloids, which are mostly constituted of nitrogen and are commonly employed in medicine [47]. Alkaloids are one of the most diverse classes of natural chemicals, with over 12,000 known structures. The ability of the secondary plant metabolites to inhibit the expression of both non-coding and coding genes is then used to modulate a variety of cellular pathways, including MAPK [48, 49]; Table 1 contains several examples.

Table 1 Some examples of naturally occurring biologically active compounds to regulate the MAPK in parallel with another associated pathway involved in cancer invasion and progression
Full size table

For the suppression of cell proliferation in pancreatic cells, the NF-kB and MAPK survival pathways were empirically suppressed using CAPE (caffeic acid phenethyl ester) and U0126. CAPE only activated the apoptosis mechanism after autophagy was inhibited [48, 50]; in MIAPaCa-2 cells, this occurred in a caspase-dependent fashion, but in PANC-1 cells, it occurred in a caspase-independent mode [51]. CAPE is a complicated therapeutic agent that affects not only programmed cell death but also angiogenesis and EMT pathways [52]. Furthermore, this study emphasizes the significance of selecting the appropriate cell culture model and understanding the characteristics of the cell lines to collect meaningful results [51].

Apigenin, a flavonoid is another chemopreventive drug that suppresses the development of choriocarcinoma cells by regulating the ERK1/2 MAPK and PI3K/AKT signal transduction mechanisms. The presence of ERK1/2 inhibitors and PI3K/AKT inhibitors enhances these effects [53].

Kaempferol, another flavanol, has been linked to angiogenesis inhibition by affecting HIF-1 and VEGFR2 in endothelial cells via a process involving PI3K/AKT/mTOR and ERK/p38. Endothelial cells were treated with kaempferol in combination with a p38 inhibitor (SB203580) or an ERK inhibitor (PD98059), and the therapeutic effectiveness of kaempferol was found to be enhanced [88].

Coumestrol, phaseol, and isotrifoliol have been shown significant anti-inflammatory effects on LPS (Lipopolysaccharide)-induced RAW264.7 macrophages, mostly via TLR/MAPK signaling and TLR (Toll-like receptors)/NF-kB [89]. Coumestrol, a phytoestrogen, inhibits cell proliferation through modulating MAPK-related genes and an AKT-related compensatory mechanism [54]. Quercetin, a flavonol molecule found in high concentrations, has been shown to inhibit choriocarcinoma growth by interfering with PI3K and MAPK signal transduction. Furthermore, quercetin enhanced the chemotherapeutic effects of paclitaxel and cisplatin in the cell lines of choriocarcinoma (JEG3 and JAR) [55].

Isoflavones were recently thought to be promising anti-cancer medicines [90]. The consequences of genistein and novasoy were studied in endometrial cancer cells. These cells were found to have an antiproliferative impact associated with the activation of the MAPK and AKT/mTOR signaling pathways [58]. Furthermore, it has been established that genistein can reduce ER expression while increasing PR (progesterone receptor) expression [58]. In melanoma cells, genistein inhibits the proliferation of cells, migration and invasion, via the MAPK and FAK/paxillin pathways [57]. Furthermore, 5,6,7,3′,4′,5′-hexamethoxyflavone which is a polymethoxyflavone has been demonstrated to impede the cellular proliferation of triple-negative breast cancer (through MAPK/AKT targeting) and cell-cycle arresting [91].

Resveratrol is a controversial natural chemical with anti-tumour properties that is being investigated as a possible treatment possibility [92]. Resveratrol can preferentially trigger autophagy and apoptosis in the T-cell acute lymphoblastic leukaemia cells via suppression of mTOR/AKT/4E-BP1/p70S6K and initiation of p38-MAPK pathways [93].

Escin, a combination of triterpene and saponins derived from the Aesculus hippocastanum, has anti-tumor ability via autophagy and apoptosis regulation via ROS/p38 MAPK signaling [94].

Furthermore, 21-methylmelianodiol (21-MMD) obtained from Poncirus trifoliata, has anti-tumor effect in the cancer of the lung via interfering with MAPK signaling and AKT/ PI3K/AMPK signaling it is also related to multi-drug resistance reversal by reducing the expressions of P-gp/MDR1 (P-glycoprotein/multidrug resistance protein 1) [95].

Toosendanin is a natural insecticide that has been shown in lung cancer models to switch EMT markers expression via ERK/Snail signaling pathway [96].

Sulforaphane (SFN) is another natural chemical that has been studied for its potential use in the treatment of OS (osteosarcoma) [97]. This isothiocyanate chemical is derived from vegetables such as broccoli, Brussels sprouts, and cabbage. Sawai et al. examined the effects of SFN on the cell line of murine osteosarcoma (LM8). These cells were grown with SFN at various doses, which caused improved cell populations in the phase of G2/M. The combination of 2 Gy of radiation and SFN inhibited the phosphorylation of ERK and AKT. SFN was also shown to cause apoptosis via G2/M phase arrest and to decrease ERK and AKT activation [98]. Another study found that SFN caused genomic instability in the cell lines of MG63 OS by mitotic and nuclear abnormalities, clastogenicity and DNA breaks. Increased production of micronuclei and apoptotic bodies indicated viability loss. SFN might be an effective molecular targeting chemotherapeutic drug for ovarian cancer [99].

Figure 2 depicts some of the most essential areas of action of those natural chemicals and Table 1 presents the most representative chemical structures of bioactive compounds which modulate the Ras-ERK cascade.

Fig. 2
figure 2

Depiction of some of the bioactive natural products and their important areas of action in the Ras-ERK cascade

Full size image

Natural bioactive compounds as kinase inhibitors

Plants have a vast store of natural bioactive compounds with beneficial effects on human health [46, 100,101,102]. According to one study, 80% of the world's population still uses plant-derived medications to meet their healthcare needs [45, 103, 104]. Traditional medicine utilizes a combination of many ingredients; however, the ingredients might not show activities as a single entity but sometimes a combination of ingredients plays an important role in having synergistic effects and modulating other proteins which improve the efficacy of the bioactive principle [105,106,107]. Protein kinase inhibitors have recently been shown to be chemically linked to a class of plant chemicals known as sesquiterpenes, alkaloids, flavonoids, polyphenolics, and diterpenoids, which are present in a variety of fruits, vegetables, and medicinal plants and have anti-cancer properties [44, 108]. The FDA authorized 1453 new chemical entities in 2013 with natural products or analogues of natural substances accounting for 40% of the total [109].

DLW (Danggui Longhui Wan) is a common traditional Chinese herbal medicine to treat chronic myeloid leukemia (CML) [110]. It’s made up of eleven different plant ingredients. Only indirubin was shown to be effective against CML during the hunt for the active chemical. The other ten compounds were all inactive. Indirubin is an effective inhibitor of CDKs (cyclin-dependent kinases), which are important in cell division. Because tumor cells rely largely on cell division, inhibiting CDKs will prevent cell division progression and therefore tumor development. Indirubin, on the other hand, performed well but was hard to absorb in the digestive system [111]. Gliotoxin is a sulfur-containing mycotoxin generated by a pathogenic fungus such as Aspergillus fumigatus that inhibits Ras protein and hence cell development [112]. Magnolin, a natural chemical present in Magnolia flos, inhibits cell proliferation caused by tumor promoters such as EGF (epidermal growth factor) and focuses on ERK1 and ERK2 [113].

Discussions

There is proof that the usage of natural compounds originating from microbes, animals, or plants for medical purposes goes back to the Neanderthal epoch [114, 115]. People have gathered knowledge and become an expert in their applications due to various biological activities of isolated natural items [116,117,118]. The invention of the chemical structure aided the manufacturing of the essential compounds rather than separating them from natural sources [119]. This process was also less expensive and allowed for the use of the active element of the medicinal plant rather than the basic plant extraction [106, 107]. Marketed medications like camptothecin, artemisinin, maytansine, lovastatin, penicillin, paclitaxel, silibinin and reserpine were either indirectly or directly developed from natural compounds [120]. Natural goods are now being viewed as a viable substitute for manufactured medications. These natural compounds can be found in a variety of sources, including plants, microbes, and fungus [118]. Today, pharmaceutical research is shifting away toward multiple target approaches than single-molecule target techniques.

Natural products have been shown to initiate apoptosis and chemosensitive cell lines that were previously resistant to conventional treatments [121,122,123]. The heterogeneity of natural compounds' inefficiency found in the cell line-centred tests and rodent models used throughout the phase of the drug discovery, which leads to the ultimate effectiveness in patients, is a significant barrier in the creation of a particular inhibitor [124].

Since the first kinase inhibitor was developed in the 1980s, more than 40 kinase inhibitors have been approved by the FDA for the treatment of malignant cells such as lung and breast cancer cells. Furthermore, around 150 kinase-targeted medicines are in clinical trials, and preclinical research is also going on numerous kinase-specific inhibitors [125]. Despite the promising anti-tumour activity and survival improvements gained by licensed RAF, MEK, and ERK inhibitors, drug resistance is the main limitation of the development of new MAPK pathway inhibitors [125]. The underlying processes, which are often associated with genomic instability and cancer heterogeneity, are largely associated with the compensatory initiation of the upstream component. More research into the MAPK pathway has led to the hypothesis that targets the downstream kinase of the ERK, and also the combination of ERK inhibition with MEK and RAF inhibition may be advantageous [125].

B-Raf is in therapeutic use among a few serine/threonine kinases inhibitors. These inhibitors of serine/threonine kinase for MAPK Aurora kinases, and CK2 and mTOR are being developed for therapeutic use [126]. We concentrated on the pathways of the canonical primary signal transduction depicted in Fig. 1. The emphasis is primarily on natural products made from plant sources, particularly flavonoids. Protein kinase B, cyclin-dependent kinases, polo-like kinase I, and other enzymes are affected. CDKs have also been targeted using natural chemicals derived from sources other than plants, such as marine creatures. New microorganisms that can survive in extreme environmental conditions called “extremophiles” have opened new perspectives in the biotechnology/pharmaceutical industry with anti-cancer therapeutic potential by blocking the cell cycle. They also have antioxidant effects. It has been observed that most extremophilic microorganisms have an increased resistance to ultraviolet radiation and can be used to develop anticancer drugs [127]. This might be a new source for developing more strong kinase inhibitors.

Limitations and future perspectives

This review has some limitations that need to be addressed in the future, such as the lack of in vivo studies that provide mechanistic perspectives on molecular interactions and targets of action of phytochemicals included in this study. Also, future in silico studies such as molecular docking may address molecular targets for a better understanding of phytochemical interactions in different signaling pathways.

Another limitation is the lack of large-scale and well-controlled clinical trials to validate the efficacy of these molecular targets, their adverse effects, and the safety of their administration for the treatment of cancer.

Although natural products show excellent results in vitro, the development of cytostatic drugs in them is a complex process, except for a few. The therapeutic advantage of these natural products is their minimal toxicity and reduced side effects [92, 128, 129]. But natural bioactive compounds can interact with many proteins, which is why it is very important to elucidate the mechanisms of action of natural products, especially those that are used in our diet [130].

In recent decades, kinase inhibitors have received more attention in search of new drugs and bioactive natural compounds that target a wide range of kinases. However, there are some therapeutic limitations of natural bioactive compounds, such as poor solubility, complexity, and biodisponibility [131,132,133]. Therefore, to overcome these clinical pitfalls and to obtain food supplements officially approved by the competent authorities, a comprehensive quality analysis must be performed in terms of bioavailability, efficacy, safety, composition, technological manufacturing processes, pharmaceutical regulatory practices and compliance with international standards.

Conclusion

At the time, too many diverse biological features are known, making it easy to infer that they are to blame for the reported health impacts. Each ingredient in plant extracts is not effective enough to account for successful cancer treatment on its own. There is a growing body of evidence that protein kinase inhibitors can be isolated from sources other than plants. Protein kinase inhibitors have recently been obtained from marine sources. This is a novel and promising strategy for discovering new forms of kinase inhibitors. However, there are a lot of other factors, such as genetics, environment, physical activity, dietary habits, and so on, and food-related considerations alone are insufficient. When a specific molecule would be targeted, which may pave the door for larger use of flavonoids, simply because they interfere with multiple cellular ‘war fields’. When employed appropriately, this finding might lead to an effective anticancer treatment in the future.

Availability of data and materials

Yes.

References

  1. Sell S, Nicolini A, Ferrari P, Biava PM. Cancer: a problem of developmental biology; scientific evidence for reprogramming and differentiation therapy. Curr Drug Targets. 2016;17(10):1103–10.

    Article  CAS  PubMed  Google Scholar 

  2. Sharifi-Rad J, Quispe C, Bouyahya A, El Menyiy N, El Omari N, Shahinozzaman M, Ara Haque Ovey M, Koirala N, Panthi M, Ertani A, et al. Ethnobotany, phytochemistry, biological activities, and health-promoting effects of the Genus Bulbophyllum. Evid Based Complement Alternat Med. 2022;2022:6727609.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Quetglas-Llabrés MM, Quispe C, Herrera-Bravo J, Catarino MD, Pereira OR, Cardoso SM, Dua K, Chellappan DK, Pabreja K, Satija S, et al. Pharmacological properties of bergapten: mechanistic and therapeutic aspects. Oxid Med Cell Longev. 2022;2022:8615242.

    Article  PubMed  PubMed Central  Google Scholar 

  4. GBD 2019 Colorectal Cancer Collaborators. Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol. 2022. https://doi.org/10.1016/S2468-1253(22)00044-9.

    Article  Google Scholar 

  5. Kato Y, Maeda T, Suzuki A, Baba Y. Cancer metabolism: new insights into classic characteristics. Jpn Dent Sci Rev. 2018;54(1):8–21.

    Article  PubMed  Google Scholar 

  6. Sharifi-Rad J, Quispe C, Patra JK, Singh YD, Panda MK, Das G, Adetunji CO, Michael OS, Sytar O, Polito L, et al. Paclitaxel: application in modern oncology and nanomedicine-based cancer therapy. Oxid Med Cell Longev. 2021;2021:3687700.

    PubMed  PubMed Central  Google Scholar 

  7. Docea AO, Mitrut P, Grigore D, Pirici D, Calina DC, Gofita E. Immunohistochemical expression of TGF beta (TGF-beta), TGF beta receptor 1 (TGFBR1), and Ki67 in intestinal variant of gastric adenocarcinomas. Rom J Morphol Embryol. 2012;53(3):683–92.

    PubMed  Google Scholar 

  8. Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, Rusu A, Irimie A, Atanasov AG, Slaby O. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers. 2019;11(10):1618.

    Article  CAS  PubMed Central  Google Scholar 

  9. Cainap C, Nagy V, Seicean A, Gherman A, Laszlo I, Lisencu C, Nadim AH, Constantin A-M, Cainap S. Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer. J BUON. 2016;21:349–59.

    PubMed  Google Scholar 

  10. Jain D, Chaudhary P, Varshney N, Bin Razzak KS, Verma D, Zahra TRK, Janmeda P, Sharifi-Rad J, Dastan SD, Mahmud S, et al. Tobacco smoking and liver cancer risk: potential avenues for carcinogenesis. J Oncol. 2021;2021:11.

    Article  CAS  Google Scholar 

  11. Mitrut P, Docea AO, Kamal AM, Mitrut R, Calina D, Gofita E, Padureanu V, Gruia C, Streba L. Colorectal cancer and inflammatory bowel disease. Houston: Intech; 2016.

    Book  Google Scholar 

  12. Dhyani P, Quispe C, Sharma E, Bahukhandi A, Sati P, Attri DC, Szopa A, Sharifi-Rad J, Docea AO, Mardare I, et al. Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell Int. 2022;22(1):206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Semwal P, Painuli S, Abu-Izneid T, Rauf A, Sharma A, Daştan SD, Kumar M, Alshehri MM, Taheri Y, Das R, et al. Diosgenin: an updated pharmacological review and therapeutic perspectives. Oxid Med Cell Longev. 2022;2022:1035441.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zijlstra A, Von Lersner A, Yu D, Borrello L, Oudin M, Kang Y, Sahai E, Fingleton B, Stein U, Cox TR, et al. The importance of developing therapies targeting the biological spectrum of metastatic disease. Clin Exp Metastasis. 2019;36(4):305–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Buga AM, Docea AO, Albu C, Malin RD, Branisteanu DE, Ianosi G, Ianosi SL, Iordache A, Calina D. Molecular and cellular stratagem of brain metastases associated with melanoma. Oncol Lett. 2019;17(5):4170–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, Baba Y. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013;13(1):89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Plotnikov A, Zehorai E, Procaccia S. Seger R (2011) The MAPK cascades signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta Mol Cell Res. 1813;9:1619–33.

    Google Scholar 

  18. Liu F, Yang X, Geng M, Huang M. Targeting ERK, an Achilles’ heel of the MAPK pathway, in cancer therapy. Acta Pharm Sin B. 2018;8(4):552–62.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ali ES, Rychkov GY, Barritt GJ. Targeting Ca(2+) signaling in the initiation, promotion and progression of hepatocellular carcinoma. Cancers (Basel). 2020;12(10):2755.

    Article  CAS  Google Scholar 

  20. Sutoo S, Maeda T, Suzuki A, Kato Y. Adaptation to chronic acidic extracellular pH elicits a sustained increase in lung cancer cell invasion and metastasis. Clin Exp Metastasis. 2020;37(1):133–44.

    Article  CAS  PubMed  Google Scholar 

  21. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS, Saghafinia S. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321-337. e310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seles M, Hutterer GC, Kiesslich T, Pummer K, Berindan-Neagoe I, Perakis S, Schwarzenbacher D, Stotz M, Gerger A, Pichler M. Current insights into long non-coding RNAs in renal cell carcinoma. Int J Mol Sci. 2016;17(4):573.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Zlatian OM, Comanescu MV, Rosu AF, Rosu L, Cruce M, Gaman AE, Calina CD, Sfredel V. Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer. Rom J Morphol Embryol. 2015;56(1):175–81.

    PubMed  Google Scholar 

  24. Ianoși SL, Batani A, Ilie MA, Tampa M, Georgescu SR, Zurac S, Boda D, Ianosi NG, Neagoe D, Calina D, et al. Non-invasive imaging techniques for the in vivo diagnosis of Bowen’s disease: three case reports. Oncol Lett. 2019;17(5):4094–101.

    PubMed  PubMed Central  Google Scholar 

  25. Braicu C, Catana C, Calin A G, Berindan-Neagoe I. NCRNA combined therapy as future treatment option for cancer. Curr Pharm Des. 2014;20(42):6565–74.

    Article  CAS  PubMed  Google Scholar 

  26. Braicu C, Zimta A-A, Harangus A, Iurca I, Irimie A, Coza O, Berindan-Neagoe I. The function of non-coding RNAs in lung cancer tumorigenesis. Cancers. 2019;11(5):605.

    Article  CAS  PubMed Central  Google Scholar 

  27. Braicu C, Pileczki V, Irimie A, Berindan-Neagoe I. p53siRNA therapy reduces cell proliferation, migration and induces apoptosis in triple negative breast cancer cells. Mol Cell Biochem. 2013;381(1–2):61–8.

    Article  CAS  PubMed  Google Scholar 

  28. Ganapathi MK, Jones WD, Sehouli J, Michener CM, Braicu IE, Norris EJ, Biscotti CV, Vaziri SA, Ganapathi RN. Expression profile of COL2A1 and the pseudogene SLC6A10P predicts tumor recurrence in high-grade serous ovarian cancer. Int J Cancer. 2016;138(3):679–88.

    Article  CAS  PubMed  Google Scholar 

  29. Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7(5):1016–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Sani TA, Mohammadpour E, Mohammadi A, Memariani T, Yazdi MV, Rezaee R, Calina D, Docea AO, Goumenou M, Etemad L, et al. Cytotoxic And apoptogenic properties Of Dracocephalum Kotschyi aerial part different fractions on calu-6 and mehr-80 lung cancer cell lines. Farmacia. 2017;65(2):189–99.

    CAS  Google Scholar 

  31. Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015;5(4): a006098.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Shortt J, Johnstone RW. Oncogenes in cell survival and cell death. Cold Spring Harb Perspect Biol. 2012;4(12): a009829.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ungefroren H. Autocrine TGF-β in cancer: review of the literature and caveats in experimental analysis. Int J Mol Sci. 2021;22(2):977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel). 2017;9(5):52.

    Article  CAS  Google Scholar 

  35. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Debela DT, Muzazu SG, Heraro KD, Ndalama MT, Mesele BW, Haile DC, Kitui SK, Manyazewal T. New approaches and procedures for cancer treatment: current perspectives. SAGE Open Med. 2021;9:20503121211034370–20503121211034370.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Silk JD, Abbott RJM, Adams KJ, Bennett AD, Brett S, Cornforth TV, Crossland KL, Figueroa DJ, Jing J, O’Connor C, et al. Engineering cancer antigen-specific T cells to overcome the immunosuppressive effects of TGF-β. J Immunol. 2022;208(1):169–80.

    Article  CAS  PubMed  Google Scholar 

  38. Ali ES, Sahu U, Villa E, O’Hara BP, Gao P, Beaudet C, Wood AW, Asara JM, Ben-Sahra I. ERK2 Phosphorylates PFAS to mediate posttranslational control of de novo purine synthesis. Mol Cell. 2020;78(6):1178-1191.e1176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21(3):1102.

    Article  CAS  PubMed Central  Google Scholar 

  40. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75(1):50–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sharifi-Rad J, Quispe C, Butnariu M, Rotariu LS, Sytar O, Sestito S, Rapposelli S, Akram M, Iqbal M, Krishna A, et al. Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell Int. 2021;21(1):318–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Taheri Y, Quispe C, Herrera-Bravo J, Sharifi-Rad J, Ezzat SM, Merghany RM, Shaheen S, Azmi L, Prakash Mishra A, Sener B, et al. Urtica dioica-derived phytochemicals for pharmacological and therapeutic applications. Evid Based Complement Alternat Med. 2022;2022:4024331.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Painuli S, Quispe C, Herrera-Bravo J, Semwal P, Martorell M, Almarhoon ZM, Seilkhan A, Ydyrys A, Rad JS, Alshehri MM, et al. Nutraceutical profiling, bioactive composition, and biological applications of Lepidium sativum L. Oxid Med Cell Longev. 2022;2022:2910411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Baier A, Szyszka R. Compounds from natural sources as protein kinase inhibitors. Biomolecules. 2020;10(11):1546.

    Article  CAS  PubMed Central  Google Scholar 

  45. Rajib H, Muhammad Torequl I, Pranta R, Divya J, Abu Saim Mohammad S, Lutfun N, Anupam Das T, Satyajit S, Seyed Abdulmajid A, Miquel M, et al. Amentoflavone, new hope against SARS-CoV-2: an outlook through its scientific records and an in silico study. Pharmacogn Res. 2021. https://doi.org/10.5530/pres.13.3.7.

    Article  Google Scholar 

  46. Hossain R, Sarkar C, Hassan SMH, Khan RA, Arman M, Ray P, Islam MT, Daştan SD, Sharifi-Rad J, Almarhoon ZM, et al. In silico screening of natural products as potential inhibitors of SARS-CoV-2 using molecular docking simulation. Chin J Integr Med. 2021. https://doi.org/10.1007/s11655-021-3504-5.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hossain R, Quispe C, Saikat ASM, Jain D, Habib A, Janmeda P, Islam MT, Radha SD, Kumar M, et al. Biosynthesis of secondary metabolites based on the regulation of microRNAs. Biomed Res Int. 2022;2022:9349897.

    PubMed  PubMed Central  Google Scholar 

  48. Budisan L, Gulei D, Zanoaga OM, Irimie AI, Sergiu C, Braicu C, Gherman CD, Berindan-Neagoe I. Dietary intervention by phytochemicals and their role in modulating coding and non-coding genes in cancer. Int J Mol Sci. 2017;18(6):1178.

    Article  PubMed Central  CAS  Google Scholar 

  49. Braicu C, Mehterov N, Vladimirov B, Sarafian V, Nabavi SM, Atanasov AG, Berindan-Neagoe I. Nutrigenomics in cancer: revisiting the effects of natural compounds. Semin Cancer Biol. 2017;46:84–106.

    Article  CAS  PubMed  Google Scholar 

  50. Budisan L, Gulei D, Jurj A, Braicu C, Zanoaga O, Cojocneanu R, Pop L, Raduly L, Barbat A, Moldovan A, et al. Inhibitory effect of CAPE and Kaempferol in colon cancer cell lines-possible implications in new therapeutic strategies. Int J Mol Sci. 2019;20(5):1199.

    Article  CAS  PubMed Central  Google Scholar 

  51. Papademetrio DL, Lompardia SL, Simunovich T, Costantino S, Mihalez CY, Cavaliere V, Alvarez E. Inhibition of survival pathways MAPK and NF-kB triggers apoptosis in pancreatic ductal adenocarcinoma cells via suppression of autophagy. Target Oncol. 2016;11(2):183–95.

    Article  PubMed  Google Scholar 

  52. Gherman C, Braicu OL, Zanoaga O, Jurj A, Pileczki V, Maralani M, Drigla F, Braicu C, Budisan L, Achimas-Cadariu P, et al. Caffeic acid phenethyl ester activates pro-apoptotic and epithelial-mesenchymal transition-related genes in ovarian cancer cells A2780 and A2780cis. Mol Cell Biochem. 2016;413(1–2):189–98.

    Article  CAS  PubMed  Google Scholar 

  53. Lim W, Park S, Bazer FW, Song G. Apigenin reduces survival of choriocarcinoma cells by inducing apoptosis via the PI3K/AKT and ERK1/2 MAPK pathways. J Cell Physiol. 2016;231(12):2690–9.

    Article  CAS  PubMed  Google Scholar 

  54. Lim W, Jeong M, Bazer FW, Song G. coumestrol inhibits proliferation and migration of prostate cancer cells by regulating AKT, ERK1/2, and JNK MAPK cell signaling cascades. J Cell Physiol. 2017;232(4):862–71.

    Article  CAS  PubMed  Google Scholar 

  55. Lim W, Yang C, Park S, Bazer FW, Song G. Inhibitory effects of quercetin on progression of human choriocarcinoma cells are mediated through PI3K/AKT and MAPK signal transduction cascades. J Cell Physiol. 2017;232(6):1428–40.

    Article  CAS  PubMed  Google Scholar 

  56. Kim GD. Kaempferol inhibits angiogenesis by suppressing HIF-1alpha and VEGFR2 activation via ERK/p38 MAPK and PI3K/Akt/mTOR signaling pathways in endothelial cells. Prev Nutr Food Sci. 2017;22(4):320–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cui S, Wang J, Wu Q, Qian J, Yang C, Bo P. Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways. Oncotarget. 2017;8(13):21674–91.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Malloy KM, Wang J, Clark LH, Fang Z, Sun W, Yin Y, Kong W, Zhou C, Bae-Jump VL. Novasoy and genistein inhibit endometrial cancer cell proliferation through disruption of the AKT/mTOR and MAPK signaling pathways. Am J Transl Res. 2018;10(3):784–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ge J, Liu Y, Li Q, Guo X, Gu L, Ma ZG, Zhu YP. Resveratrol induces apoptosis and autophagy in T-cell acute lymphoblastic leukemia cells by inhibiting Akt/mTOR and activating p38-MAPK. Biomed Environ Sci. 2013;26(11):902–11.

    CAS  PubMed  Google Scholar 

  60. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PVT, Martins N, Sharifi-Rad J. Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6(3):91.

    Article  CAS  PubMed Central  Google Scholar 

  61. Zhu J, Yu W, Liu B, Wang Y, Shao J, Wang J, Xia K, Liang C, Fang W, Zhou C, et al. Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 2017;8(10): e3113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Aldonza MB, Hong JY, Bae SY, Song J, Kim WK, Oh J, Shin Y, Lee SH, Lee SK. Suppression of MAPK signaling and reversal of mTOR-dependent MDR1-associated multidrug resistance by 21alpha-methylmelianodiol in lung cancer cells. PLoS ONE. 2015;10(6): e0127841.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Luo W, Liu X, Sun W, Lu JJ, Wang Y, Chen X. Toosendanin, a natural product, inhibited TGF-β1-induced epithelial-mesenchymal transition through ERK/Snail pathway. Phytother Res. 2018;32(10):2009–20.

    Article  CAS  PubMed  Google Scholar 

  64. Shao J, Wang C, Li L, Liang H, Dai J, Ling X, Tang H. Luteoloside inhibits proliferation and promotes intrinsic and extrinsic pathway-mediated apoptosis involving MAPK and mTOR signaling pathways in human cervical cancer cells. Int J Mol Sci. 2018;19(6):1664.

    Article  PubMed Central  CAS  Google Scholar 

  65. Liang RR, Zhang S, Qi JA, Wang ZD, Li J, Liu PJ, Huang C, Le XF, Yang J, Li ZF. Preferential inhibition of hepatocellular carcinoma by the flavonoid Baicalein through blocking MEK-ERK signaling. Int J Oncol. 2012;41(3):969–78.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang XJ, Jia SS. Fisetin inhibits laryngeal carcinoma through regulation of AKT/NF-kappaB/mTOR and ERK1/2 signaling pathways. Biomed Pharmacother. 2016;83:1164–74.

    Article  CAS  PubMed  Google Scholar 

  67. Lim W, Park S, Bazer FW, Song G. Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways. J Cell Biochem. 2017;118(5):1118–31.

    Article  CAS  PubMed  Google Scholar 

  68. Mao J, Yang H, Cui T, Pan P, Kabir N, Chen D, Ma J, Chen X, Chen Y, Yang Y. Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT. Eur J Pharmacol. 2018;832:39–49.

    Article  CAS  PubMed  Google Scholar 

  69. Jain D, Murti Y, Khan WU, Hossain R, Hossain MN, Agrawal KK, Ashraf RA, Islam MT, Janmeda P, Taheri Y, et al. Roles of therapeutic bioactive compounds in hepatocellular carcinoma. Oxid Med Cell Longev. 2021;2021:9068850.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Oi N, Chen H, Ok Kim M, Lubet RA, Bode AM, Dong Z. Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res (Phila). 2012;5(9):1103–14.

    Article  CAS  Google Scholar 

  71. Kang HM, Park BS, Kang HK, Park HR, Yu SB, Kim IR. Delphinidin induces apoptosis and inhibits epithelial-to-mesenchymal transition via the ERK/p38 MAPK-signaling pathway in human osteosarcoma cell lines. Environ Toxicol. 2018;33(6):640–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lin M, Bi H, Yan Y, Huang W, Zhang G, Zhang G, Tang S, Liu Y, Zhang L, Ma J, et al. Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway. Oncotarget. 2017;8(14):23436–47.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Singh VJ, Sharma B, Chawla PA. Recent developments in mitogen activated protein kinase inhibitors as potential anticancer agents. Bioorg Chem. 2021;114: 105161.

    Article  CAS  PubMed  Google Scholar 

  74. Pi J, Jiang J, Cai H, Yang F, Jin H, Yang P, Cai J, Chen ZW. GE11 peptide conjugated selenium nanoparticles for EGFR targeted oridonin delivery to achieve enhanced anticancer efficacy by inhibiting EGFR-mediated PI3K/AKT and Ras/Raf/MEK/ERK pathways. Drug Deliv. 2017;24(1):1549–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lev-Ari S, Starr A, Vexler A, Karaush V, Loew V, Greif J, Fenig E, Aderka D, Ben-Yosef R. Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity. Anticancer Res. 2006;26(6B):4423–30.

    CAS  PubMed  Google Scholar 

  76. Hao W, Yuan X, Yu L, Gao C, Sun X, Wang D, Zheng Q. Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways. Sci Rep. 2015;5:10336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pan C, Hu Y, Li J, Wang Z, Huang J, Zhang S, Ding L. Estrogen receptor-alpha36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer. PLoS ONE. 2014;9(8): e104459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Zhang M, Cai S, Zuo B, Gong W, Tang Z, Zhou D, Weng M, Qin Y, Wang S, Liu J, et al. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway. Tumour Biol. 2017;39(5):1010428317698359.

    PubMed  Google Scholar 

  79. Lee CH, Ying TH, Chiou HL, Hsieh SC, Wen SH, Chou RH, Hsieh YH. Alpha-mangostin induces apoptosis through activation of reactive oxygen species and ASK1/p38 signaling pathway in cervical cancer cells. Oncotarget. 2017;8(29):47425–39.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Mi Jeong S, Davaatseren M, Kim W, Sung Kwang P, Kim SH, Haeng Jeon H, Myung Sunny K, Kim YS, Dae Young K. Vitisin A suppresses LPS-induced NO production by inhibiting ERK, p38, and NF-kappaB activation in RAW 2647 cells. Int Immunopharmacol. 2009;9(3):319–23.

    Article  CAS  Google Scholar 

  81. Asami Y, Kakeya H, Komi Y, Kojima S, Nishikawa K, Beebe K, Neckers L, Osada H. Azaspirene, a fungal product, inhibits angiogenesis by blocking Raf-1 activation. Cancer Sci. 2008;99(9):1853–8.

    Article  CAS  PubMed  Google Scholar 

  82. Polier G, Neumann J, Thuaud F, Ribeiro N, Gelhaus C, Schmidt H, Giaisi M, Köhler R, Müller WW, Proksch P, et al. The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem Biol. 2012;19(9):1093–104.

    Article  CAS  PubMed  Google Scholar 

  83. Zhao A, Lee SH, Mojena M, Jenkins R, Patrick DR, Huber HE, Goetz MA, Hensens OD, Zink DL, Vilella D, et al. Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK. J Antibiot. 1999;52(12):1086–94.

    Article  CAS  Google Scholar 

  84. Lee C-J, Lee M-H, Yoo S-M, Choi K-I, Song J-H, Jang J-H, Oh S-R, Ryu H-W, Lee H-S, Surh Y-J, et al. Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway. BMC Cancer. 2015;15(1):576.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Jeon S, Kim M-M. Tomatidine inhibits cell invasion through the negative modulation of gelatinase and inactivation of p38 and ERK. Chem Biol Interact. 2019;313: 108826.

    Article  CAS  PubMed  Google Scholar 

  86. Lim DY, Shin SH, Lee M-H, Malakhova M, Kurinov I, Wu Q, Xu J, Jiang Y, Dong Z, Liu K, et al. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer. Oncotarget. 2016;7(23):35001.

    Article  PubMed Central  Google Scholar 

  87. Zhi TX, Liu KQ, Cai KY, Zhao YC, Li ZW, Wang X, He XH, Sun XY. Anti-lung cancer activities of 1,2,3-triazole curcumin derivatives via regulation of the MAPK/NF-κB/STAT3 signaling pathways. ChemMedChem. 2021. https://doi.org/10.1002/cmdc.202100676.

    Article  PubMed  Google Scholar 

  88. Kim GD. Kaempferol inhibits angiogenesis by suppressing HIF-1α and VEGFR2 activation via ERK/p38 MAPK and PI3K/Akt/mTOR signaling pathways in endothelial cells. Prev Nutr Food Sci. 2017;22(4):320–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li H, Yoon JH, Won HJ, Ji HS, Yuk HJ, Park KH, Park HY, Jeong TS. Isotrifoliol inhibits pro-inflammatory mediators by suppression of TLR/NF-κB and TLR/MAPK signaling in LPS-induced RAW264.7 cells. Int Immunopharmacol. 2017;45:110–9.

    Article  CAS  PubMed  Google Scholar 

  90. Sharifi-Rad J, Quispe C, Imran M, Rauf A, Nadeem M, Gondal TA, Ahmad B, Atif M, Mubarak MS, Sytar O, et al. Genistein: an integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev. 2021;2021:3268136.

    PubMed  PubMed Central  Google Scholar 

  91. Borah N, Gunawardana S, Torres H, McDonnell S, Van Slambrouck S. 5,6,7,3′,4′,5′-Hexamethoxyflavone inhibits growth of triple-negative breast cancer cells via suppression of MAPK and Akt signaling pathways and arresting cell cycle. Int J Oncol. 2017;51(6):1685–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sharifi-Rad J, Quispe C, Durazzo A, Lucarini M, Souto EB, Santini A, Imran M, Moussa AY, Mostafa NM, El-Shazly M, et al. Resveratrol’ biotechnological applications: enlightening its antimicrobial and antioxidant properties. J Herb Med. 2022;32: 100550.

    Article  Google Scholar 

  93. Wang N, He J, Pan C, Wang J, Ma M, Shi X, Xu Z. Resveratrol activates autophagy via the AKT/mTOR signaling pathway to improve cognitive dysfunction in rats with chronic cerebral hypoperfusion. Front Neurosci. 2019;13:859.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Zhao W, Lao Y, Liu Y, Niu J, Xiao Z, Arulselvan P, Shen J. Escin induces apoptosis in ovarian cancer cell line by triggering S-phase cell cycle arrest and p38 MAPK/ERK pathway inhibition. J King Saud Univ Sci. 2022;34(1): 101644.

    Article  Google Scholar 

  95. Munakarmi S, Chand L, Shin HB, Hussein UK, Yun B-S, Park HR, Jeong YJ. Anticancer effects of Poncirus fructus on hepatocellular carcinoma through regulation of apoptosis, migration, and invasion. Oncol Rep. 2020;44(6):2537–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fan W, Fan L, Wang Z, Yang L. Limonoids from the genus Melia (Meliaceae): phytochemistry, synthesis, bioactivities, pharmacokinetics, and toxicology. Front Pharmacol. 2022. https://doi.org/10.3389/fphar.2021.795565.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Rizzo VL, Levine CB, Wakshlag JJ. The effects of sulforaphane on canine osteosarcoma proliferation and invasion. Vet Comp Oncol. 2017;15(3):718–30.

    Article  CAS  PubMed  Google Scholar 

  98. Sawai Y, Murata H, Horii M, Koto K, Matsui T, Horie N, Tsuji Y, Ashihara E, Maekawa T, Kubo T, et al. Effectiveness of sulforaphane as a radiosensitizer for murine osteosarcoma cells. Oncol Rep. 2013;29(3):941–5.

    Article  CAS  PubMed  Google Scholar 

  99. de Ferreira Oliveria JM, Remédios C, Oliveira H, Pinto P, Pinho F, Pinho S, Costa M, Santos C. Sulforaphane induces DNA damage and mitotic abnormalities in human osteosarcoma MG-63 cells: correlation with cell cycle arrest and apoptosis. Nutr Cancer. 2014;66(2):325–34.

    Article  CAS  Google Scholar 

  100. Sharifi-Rad J, Quispe C, Shaheen S, El Haouari M, Azzini E, Butnariu M, Sarac I, Pentea M, Ramírez-Alarcón K, Martorell M, et al. Flavonoids as potential anti-platelet aggregation agents: from biochemistry to health promoting abilities. Crit Rev Food Sci Nutr. 2021. https://doi.org/10.1080/10408398.2021.1924612.

    Article  PubMed  Google Scholar 

  101. Sharifi-Rad J, Quispe C, Herrera-Bravo J, Martorell M, Sharopov F, Tumer TB, Kurt B, Lankatillake C, Docea AO, Moreira AC, et al. A pharmacological perspective on plant-derived bioactive molecules for epilepsy. Neurochem Res. 2021;46(9):2205–25.

    Article  CAS  PubMed  Google Scholar 

  102. Sharifi-Rad J, Bahukhandi A, Dhyani P, Sati P, Capanoglu E, Docea AO, Al-Harrasi A, Dey A, Calina D. Therapeutic potential of neoechinulins and their derivatives: an overview of the molecular mechanisms behind pharmacological activities. Front Nutr. 2021;8: 664197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Salehi B, Prakash Mishra A, Nigam M, Karazhan N, Shukla I, Kiełtyka-Dadasiewicz A, Sawicka B, Głowacka A, Abu-Darwish MS, Hussein Tarawneh A, et al. Ficus plants: state of the art from a phytochemical, pharmacological, and toxicological perspective. Phytother Res. 2021;35(3):1187–217.

    Article  CAS  PubMed  Google Scholar 

  104. Sharifi-Rad J, Quispe C, Herrera-Bravo J, Akram M, Abbaass W, Semwal P, Painuli S, Konovalov DA, Alfred MA, Kumar NVA, et al. Phytochemical constituents, biological activities, and health-promoting effects of the Melissa officinalis. Oxid Med Cell Longev. 2021;2021:6584693.

    Google Scholar 

  105. Zhou X, Seto SW, Chang D, Kiat H, Razmovski-Naumovski V, Chan K, Bensoussan A. Synergistic effects of Chinese herbal medicine: a comprehensive review of methodology and current research. Front Pharmacol. 2016;7:201–201.

    PubMed  PubMed Central  Google Scholar 

  106. Sharifi-Rad J, Quispe C, Rahavian A, Pereira Carneiro JN, Rocha JE, Alves Borges Leal AL, Bezerra Morais Braga MF, Melo Coutinho HD, Ansari Djafari A, Alarcón-Zapata P, et al. Bioactive compounds as potential agents for sexually transmitted diseases management: a review to explore molecular mechanisms of action. Front Pharmacol. 2021. https://doi.org/10.3389/fphar.2021.674682.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Salehi B, Rescigno A, Dettori T, Calina D, Docea AO, Singh L, Cebeci F, Özçelik B, Bhia M, Dowlati Beirami A, et al. Avocado-soybean unsaponifiables: a panoply of potentialities to be exploited. Biomolecules. 2020;10(1):130.

    Article  CAS  PubMed Central  Google Scholar 

  108. Hossain R, Quispe C, Herrera-Bravo J, Beltrán JF, Islam MT, Shaheen S, Cruz-Martins N, Martorell M, Kumar M, Sharifi-Rad J, et al. Neurobiological promises of the bitter diterpene lactone andrographolide. Oxid Med Cell Longev. 2022;2022:3079577.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Guerra B, Issinger O-G. Natural compounds and derivatives as Ser/Thr protein kinase modulators and inhibitors. Pharmaceuticals (Basel). 2019;12(1):4.

    Article  CAS  Google Scholar 

  110. Lin HH, Robertson KL, Lellupitiyage Don SS, Taylor SR, Farkas ME. Chapter six - chemical modulation of circadian rhythms and assessment of cellular behavior via indirubin and derivatives. In: Chenoweth DM, editor. Methods in enzymology, vol. 639. Cambridge: Academic Press; 2020.

    Google Scholar 

  111. Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol. 2004;130(11):627–35.

    Article  CAS  PubMed  Google Scholar 

  112. Abdallah QA, Fortwendel JR. Exploration of Aspergillus fumigatus Ras pathways for novel antifungal drug targets. Front Microbiol. 2015;6:128.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Song J-H, Lee C-J, An H-J, Yoo S-M, Kang HC, Lee JY, Kim KD, Kim DJ, Lee HS, Cho Y-Y. Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells. Mol Carcinog. 2019;58(1):88–101.

    Article  CAS  PubMed  Google Scholar 

  114. Calina D, Buga AM, Mitroi M, Buha A, Caruntu C, Scheau C, Bouyahya A, El Omari N, El Menyiy N, Docea AO. The treatment of cognitive, behavioural and motor impairments from brain injury and neurodegenerative diseases through cannabinoid system modulation-evidence from in vivo studies. J Clin Med. 2020;9(8):28.

    Article  CAS  Google Scholar 

  115. Sharifi-Rad J, Quispe C, Herrera-Bravo J, Martorell M, Sharopov F, Tumer TB, Kurt B, Lankatillake C, Docea AO, Moreira AC, et al. A pharmacological perspective on plant-derived bioactive molecules for epilepsy. Neurochem Res. 2021. https://doi.org/10.1007/s11064-021-03376-0.

    Article  PubMed  Google Scholar 

  116. Sharifi-Rad J, Quispe C, Kumar M, Akram M, Amin M, Iqbal M, Koirala N, Sytar O, Kregiel D, Nicola S, et al. Hyssopus essential oil: an update of its phytochemistry, biological activities, and safety profile. Oxid Med Cell Longev. 2022;2022:8442734.

    PubMed  PubMed Central  Google Scholar 

  117. Islam MT, Quispe C, El-Kersh DM, Shill MC, Bhardwaj K, Bhardwaj P, Sharifi-Rad J, Martorell M, Hossain R, Al-Harrasi A, et al. A literature-based update on Benincasa hispida (Thunb.) Cogn.: traditional uses, nutraceutical, and phytopharmacological profiles. Oxid Med Cell Longev. 2021;2021:6349041.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Hossain R, Quispe C, Herrera-Bravo J, Islam MS, Sarkar C, Islam MT, Martorell M, Cruz-Martins N, Al-Harrasi A, Al-Rawahi A, et al. Lasia spinosa chemical composition and therapeutic potential: a literature-based review. Oxid Med Cell Longev. 2021;2021:1602437.

    PubMed  PubMed Central  Google Scholar 

  119. Salehi B, Quispe C, Chamkhi I, El Omari N, Balahbib A, Sharifi-Rad J, Bouyahya A, Akram M, Iqbal M, Docea AO, et al. Pharmacological properties of chalcones: a review of preclinical including molecular mechanisms and clinical evidence. Front Pharmacol. 2021;11:592654–592654.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ji HF, Li XJ, Zhang HY. Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Rep. 2009;10(3):194–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Safarzadeh E, Sandoghchian Shotorbani S, Baradaran B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv Pharm Bull. 2014;4(Suppl 1):421–7.

    PubMed  PubMed Central  Google Scholar 

  122. Sharifi-Rad J, Kamiloglu S, Yeskaliyeva B, Beyatli A, Alfred MA, Salehi B, Calina D, Docea AO, Imran M, Kumar NVA, et al. Pharmacological activities of psoralidin: a comprehensive review of the molecular mechanisms of action. Front Pharmacol. 2020;11:11.

    Article  Google Scholar 

  123. Baba Y, Kato Y. Deguelin, a novel anti-tumorigenic agent in human esophageal squamous cell carcinoma. EBioMedicine. 2017;26:10.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Ma C, Peng Y, Li H, Chen W. Organ-on-a-chip: a new paradigm for drug development. Trends Pharmacol Sci. 2021;42(2):119–33.

    Article  PubMed  CAS  Google Scholar 

  125. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: a 2021 update. Pharmacol Res. 2021;165: 105463.

    Article  CAS  PubMed  Google Scholar 

  126. Shepherd C, Puzanov I, Sosman JA. B-RAF inhibitors: an evolving role in the therapy of malignant melanoma. Curr Oncol Rep. 2010;12(3):146–52.

    Article  CAS  PubMed  Google Scholar 

  127. Singh OV, Gabani P. Extremophiles: radiation resistance microbial reserves and therapeutic implications. J Appl Microbiol. 2011;110(4):851–61.

    Article  CAS  PubMed  Google Scholar 

  128. Salehi B, Sharifi-Rad J, Capanoglu E, Adrar N, Catalkaya G, Shaheen S, Jaffer M, Giri L, Suyal R, Jugran AK, et al. Cucurbita plants: from farm to industry. Appl Sci-Basel. 2019;9(16):21.

    Google Scholar 

  129. Popović-Djordjević J, Quispe C, Giordo R, Kostić A, Katanić Stanković JS, Tsouh Fokou PV, Carbone K, Martorell M, Kumar M, Pintus G, et al. Natural products and synthetic analogues against HIV: a perspective to develop new potential anti-HIV drugs. Eur J Med Chem. 2022;233: 114217.

    Article  PubMed  CAS  Google Scholar 

  130. Quispe C, Herrera-Bravo J, Javed Z, Khan K, Raza S, Gulsunoglu-Konuskan Z, Daştan SD, Sytar O, Martorell M, Sharifi-Rad J, et al. Therapeutic applications of curcumin in diabetes: a review and perspective. Biomed Res Int. 2022;2022:1375892.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Tsoukalas D, Fragkiadaki P, Docea AO, Alegakis AK, Sarandi E, Vakonaki E, Salataj E, Kouvidi E, Nikitovic D, Kovatsi L, et al. Association of nutraceutical supplements with longer telomere length. Int J Mol Med. 2019;44(1):218–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Tsoukalas D, Zlatian O, Mitroi M, Renieri E, Tsatsakis A, Izotov BN, Burada F, Sosoi S, Burada E, Buga AM, et al. A novel nutraceutical formulation can improve motor activity and decrease the stress level in a murine model of middle-age animals. J Clin Med. 2021;10(4):624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Salehi B, Sestito S, Rapposelli S, Peron G, Calina D, Sharifi-Rad M, Sharopov F, Martins N, Sharifi-Rad J. Epibatidine: a promising natural alkaloid in health. Biomolecules. 2019;9(1):6.

    Article  CAS  Google Scholar 

Download references

Funding

No funding received.

Author information

Authors and Affiliations

  1. College of Medicine and Public Health, Flinders University, Bedford Park, 5042, Australia

    Eunus S. Ali

  2. Department of Bioinformatics and Computational Biology, George Mason University, Fairfax, VA, 22030, USA

    Shamima Akter

  3. Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400, Bangladesh

    Sarker Ramproshad & Banani Mondal

  4. Department of Pharmacology and Institute of New Drug Development, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea

    Thoufiqul Alam Riaz

  5. Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh

    Muhammad Torequl Islam

  6. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25100, Pakistan

    Ishaq N. Khan

  7. Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania

    Anca Oana Docea

  8. Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania

    Daniela Calina

  9. Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador

    Javad Sharifi-Rad

  10. Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong

    William C. Cho

Authors
  1. Eunus S. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shamima Akter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarker Ramproshad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Banani Mondal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thoufiqul Alam Riaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Muhammad Torequl Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ishaq N. Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anca Oana Docea
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniela Calina
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Javad Sharifi-Rad
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. William C. Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ESA, SA, SR, BM, TAR, MTI, INK, AOD, DC, JSR, WCC made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas—that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work. All authors contributed equally, have read and agreed to the published version of the manuscript. All the authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Daniela Calina, Javad Sharifi-Rad or William C. Cho.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

No competing interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ali, E.S., Akter, S., Ramproshad, S. et al. Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview. Cancer Cell Int 22, 246 (2022). https://doi.org/10.1186/s12935-022-02666-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12935-022-02666-z

Keywords

Cancer Cell International

ISSN: 1475-2867

Contact us