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

Ali, Eunus S.; Akter, Shamima; Ramproshad, Sarker; Mondal, Banani; Riaz, Thoufiqul Alam; Islam, Muhammad Torequl; Khan, Ishaq N.; Docea, Anca Oana; Calina, Daniela; Sharifi-Rad, Javad; Cho, William C.

doi:10.1186/s12935-022-02666-z

Cancer Cell International

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

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

Natural compounds	Type of cancer	Preclinical Model In vitro/cancer cell lines	Molecular targets	Effects	Refs.
Caffeic acid phenethyl ester (CAPE) + U0126	Pancreatic ductal adenocarcinoma	PANC-1 MIAPaCa-2	↓ NF-κB ↓ MAPK	↓ Cell growth, ↑ Apoptosis (PANC-1 caspase-independent mode and MIAPaCa-2 caspase-dependent)	[51]
Apigenin	Choriocarcinoma	JEG3 JAR	↓ ERK1/2 ↓ PI3K/AKT	↓ Migratory capacity ↓ Cell viability, ↑apoptosis	[53]
Coumestrol	Prostate cancer	LNCaP PC3	↓ Phosphorylation of AKT proteins ↑ Phosphorylation f P90RSK, JNK, ERK1/2, p53	↓Cell proliferation ↓migration ↑apoptosis	[54]
Quercetin	Choriocarcinoma	JEG3 JAR	↑ Phosphorylation of p38, JNK, ERK1/2, and P90RSK proteins ↓ Phosphorylation of P70S6K, AKT, S6	↓ Proliferation ↓ Invasion ↓ Cell-cycle progression	[55]
Kaempferol	Endometrial Malignant transformation	EBM-2 HUVECs	↓ VEGFR2 ↓ HIF-1α proteins ↓ Phosphorylation of and p38, ↓ ERK, ↓ Akt	↓ Angiogenesis	[56]
Genistein	Melanoma	B16F10	↓ ERK, ↓ p38, ↓ JNK, ↓ Phosphorylation of tensin-2, ↓ FAK, ↓ paxillin, ↓ vinculin	↓ Cells growth ↓ Cells migration	[57]
Genistein and Novasoy	Endometrial cancer	RL-95–2 ECC-1 cells	↑ Phosphorylation of S6 only in RL-95–2 cells ↑ Phosphorylation of the p42/44 in both cell line	↓ Cellular proliferation ↓ Cell-cycle arrest in G2 phase ↑ Apoptosis	[58]
Resveratrol	T-cell acute lymphoblastic leukemia	Jurkat (glucocorticoid resistant) and T-ALL cell lines, Molt-4 (glucocorticoid resistant)	↑ p38-MAPK ↓ Akt/p70S6K/mTOR/4E-BP1	↑ Autophagy ↑ Apoptosis	[59, 60]
Escine	Osteosarcoma	MNNG, MG-63, Saos-2, U-2OS	↑ p38	↑ Autophagy ↑ Apoptosis	[61]
Triterpenoids (21α-methylmelianodiol)	Lung cancer	A549	↓ ERK, ↓p-JNK, ↓p-ERK, ↓p38, ↓JNK, no effect on p-p38	Targeting drug resistance via P-glycoprotein (P-gp)/MDR1-association	[62]
Toosendanin	Lung cancer	H1975 and A549 cells	↓ Snail, ↓TGFβ1, ↓ Phosphorylation of ERK	Prevents TGFβ1-induced EMT and invasion, migration, and adhesion	[63]
Luteolin	Cervical cancer	Hela cells	↑ Fas, ↑ phospho-JNK, ↑ p53, ↑ phospho-p38, ↑ Bax, ↓ PARP, ↓ mTOR, ↓ Bcl-2	↓ Cellular proliferation ↑ Apoptosis	[64]
Baicalein	Hepatocellular carcinoma	HepG2cell xenograft in nude mice	↓ MEK1 ↓ Bad ↓ ERK1/2	↑ Intrinsic apoptosis	[65]
Fisetin	Laryngeal cancer	TU212 cell	↓ RAS ↓ RAF ↓ ERK1/2	↓ Cell migration ↓ Proliferation	[66]
Naringenin	Prostate cancer	LNCaP and PC3 cells	↓ p38 ERK1/2, ↓ S6, ↓ P70S6K, ↓ JNK	↑ Apoptosis, ↑ ROS ↓ Proliferation ↓ Migration	[67]
Silibinin	Hepatocellular carcinoma	Bel-7404 xenografts in nude mice Bel-7404	Combined treatment with the sorafenib ↓ Phosphorylation of ERK, STAT3, AKT, MAPK p38	↓ Proliferation ↑ Apoptosis	[68, 69]
Taxifolin	Skin cancer	skin carcinogenesis mouse model, JB6 Pþ mouse skin epidermal cells	↓ Phosphorylation of p38, EGFR, ERKs, JNKs	↓ Tumor incidence, ↓ Multiplicity in a solar UV (SUV)-induced skin carcinogenesis	[70]
Delphinidin	Osteosarcoma	HOS, U2OS, MG-63 cells	↓ Phosphorylated forms of p38 ↓ ERK	↓ Cell migration ↓ EMT ↓ Cellular proliferation ↑ Apoptosis	[71]
Parthenolide	Non-small cell lung cancer	GLC-82 cells	↓ c-Myc, ↓ B-Raf, ↓ Phosphorylation of Erk, MEK,	↓ Invasion ↓ Proliferation ↑ Apoptosis	[72, 73]
Oridonin	Esophageal cancer	KYSE-150 c xenograft KYSE-150 cancer nude mice	↓ Ras/Raf/MEK/ERK ↓ EGFR-mediated PI3K/AKT	↓ Tumor angiogenesis ↓ Angiogenesis-marker CD31 ↑ Apoptosis	[74]
Curcumin	Lung and pancreatic adenocarcinoma	p34, H1299, PC-14, Panc1	↓ Erk1/2 ↓ COX-2, ↓ EGFR	↓ Survival of cancer cell ↑ Apoptosis	[75]
Licochalcone A	Human gastric cancer	BGC-823	↑ JNK, ↑ ERK, ↑ p38 MAPK	↑ Oxidative stress ↑ Apoptosis	[76]
Pterostilbene	Breast cancer	MCF-7 MDA-MB-231	↓ Akt, ↓ ERK1/2	↑ Apoptosis ↓ Proliferation	[77]
Arctigenin	Gallbladder cancer	GBC-SD, NOZ GBC-SD	↓ EGFR, ↓ p-b-Raf, ↓ p–c-Rafp-MEK, ↓ ERK, ↓ MEK, ↓ p-AKT, ↓AKT	↑ Cancer senescence	[78]
α-mangostin	Cervical cancer	SiHa and HeLa cells and xenograft model	↑ p-ASK1, p-p38 p-MKK3/6	↑ Apoptosis	[79]
Vitisin A	Pro-tumorigenic inflammation	RAW 264.7 cells	↓ p38, ↓ERK, ↓ NF-κB	↓ Proliferation	[80]
Azaspirene	Renal carcinoma	Renal carcinoma xenograft model HUVEC	↓ Raf‐1	↓ Angiogenesis	[81]
Rocaglamide	Leukemia	Jurkat leukemic cells	↓ Raf-MEK-ERK	Targeting prohibitin 1 and 2	[82]
L-783277	Human pancreatic cancer	PSN1	↓ Phosphorylation of Ras-dependent MAP kinase	↓ Proliferation	[83]
Magnolin	Non-small cell lung carcinoma	NCI-H1975 A549	↓ ERKs/RSK2	↓NF-κB	[84]
Tomatidine	Sarcoma	HT1080	↓ ERK ↓ p38	↓ p38, ↓ ERK ↓ Modulation of gelatinase	[85]
Catechol	Lung cancer	H460 KP2	↓ ERK2	↑ c-Myc degradation ↓ ERK2	[86]
1,2,3-Triazole Curcumin	Non-small cell lung carcinoma	A549	↓ NF-κB/STAT3 ↑ mitogen-activated protein kinases	↓ Cell proliferation	[87]

↑ increase, ↓ decrease, ROS reactive oxygen species; T-ALL T-cell acute lymphoblastic leukemia; HIF Hypoxia-inducible factors; JNKs c-Jun N-terminal kinases; TGFβ transforming growth factor-beta; ERK extracellular regulated MAP kinase; p38 p38 kinase; AKT v-akt murine thymoma viral oncogene homolog 1; VEGFR vascular endothelial growth factor

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