Table 5 Therapeutic strategy targeting Mcl-1 in oral cancer (natural agents)

(−)-Epigallocatechin gallate (EGCG) polyphenol

Polyphenol

EGCG treatment led to an increase in Fas/CD95 death receptors, leading to caspase-8 activation. Reduction in levels of phosphorylated STAT3 (Tyr705 and Ser727) via interleukin-6 (IL-6) induced reduction in phosphorylated Jak1/2, following EGCG treatment. Reduction in STAT3 was associated with a reduction in Mcl-1

SAS, Cal-27, Ca9-22

[68]

Fisetin

Flavonoid

Fisetin-induced apoptotic cell death via induction of ROS, ER stress, and by disrupting the mitochondria membrane potential, which caused cytochrome c, AIF, and ENDO G release from mitochondria into the cytosol. It also led to a reduction in the expression of Mcl-1 and other apoptotic markers

HSC3

[104]

Fisetin suppressed cellular growth, via modulating the SESN2/mTOR/Mcl-1 signaling axis

MC3, Ca9.22, HN22

[105]

Honokiol (HK)

Magnolia officinalis or grandiflora

Honokiol treatment led to a reduction in Sp1 expression. It was also associated with a significant reduction in Mcl-1 and survivin and upregulation in p21 and p27 resulting in caspase-dependent apoptosis

HN-22, HSC-4

[80]

Licochalcone A

The root of Glycyrrhiza inflata

Licochalcone A treatment led to a reduction in OSCC cell growth via downregulation of Sp1 expression and subsequent regulation of Sp1 downstream proteins such as p27, p21, cyclin D1, Mcl-1, and survivin

HSC4, HN22

[106]

Licochalcone B

Retro chalcone family (root of Glycyrrhiza glabra or Glycyrrhiza inflata)

Licochalcone B treatment induced apoptosis in OSCC cells by up-regulating the death receptor and modulating the Bcl-2 family members (downregulation of Mcl-1)

HN22, HSC4

[107]

Licochalcone C

Retro chalcone family (roots of Ccardihinese licorice)

Licochalcone C treatment modulated the Jak2 activity by physically binding to it. The binding led to a reduction in phosphorylation of Jak2. This led to a reduction in phosphorylated STAT3 levels and subsequently its downstream targets such as Bcl-2, Mcl‐1, and survivin

HN22, HSC4

[69]

Dehydroandrographolide

(DA) diterpene

Andrographis paniculata (Burm.f.) Nees (family, Acanthaceae)

Dehydroandrographolide treatment induces autophagy, which is mediated via Beclin-1 by inhibiting Bcl-2, Bcl-xL, and Mcl-1. Additionally, it also led to inhibition of Akt, p38 phosphorylation, and enhanced JNK1/2 signaling pathways

SAS, OECM-1

[108]

Oridonin

Rabdosia rubescens

Oridonin treatment induced apoptosis via downregulation of Mcl-1. Mcl-1 downregulation led to the subsequent loss of MOMP and t-Bid

MC3, YD15

[109]

Evodiamine quinolone

alkaloid

Evodia fructus

Evodiamine induced apoptosis by down-regulating Mcl-1 mRNA and protein. The downregulation in Mcl-1 was due to a reduction in Akt phosphorylation

MC3, HSC4

[110]

Cryptotanshinone (CT),

tanshinones

Root of Salvia miltiorrhiza

Cryptotanshinone treatment modulated STAT3 activity and caused cell death. Reduction in STAT3 phosphorylation led to a reduction in survivin at the transcriptional level and reduced the activity of Mcl-1 via proteasomal degradation

MC3, YD15

[111]

Nitidine chloride (NC)

quaternary ammonium

alkaloid

Zanthoxylum nitidium

NC treatment led to a reduction in Mcl-1 via lysosomal-dependent degradation. The reduction in Mcl-1 following NC treatment was greater than that caused by STAT3 inhibitors

HSC3, HSC4,

In vivo

[70]

Reserpine indole alkaloid

Rauwolfia serpentina

Reserpine treatment promoted apoptosis in DMBA-induced tumors in mice, like reduction in Mcl-1. Additionally, it inhibited TGF-β signaling, DNA repair protein expression, and proliferative and invasive proteins

HEC59 (Chemical induced carcinogenesis in an animal model)

[112]

Phenethyl isothiocyanate

isothiocyanate

Cruciferous vegetable

Phenethyl isothiocyanate treatment led to cellular apoptosis and inhibited proliferation. The reduction in Mcl-1 levels was induced via GSH redox stress trigger. ROS (reduction in ΔΨm)

OC2, SCC4, SCC25

[87]

Benzyl isothiocyanate (BITC)

Plants of the mustard family

Benzyl isothiocyanate treatment led to cellular apoptosis and inhibited proliferation. It was associated with reduced mitochondrial potential ROS (reduction in ΔΨm). The reduction in Mcl-1 levels was induced via GSH redox stress trigger

OC2

[88]

Divaricoside cardiac glycosides

Strophanthus divaricatus

Divaricoside treatment suppressed the viability of OSCC cells. In addition to ROS generation, DIV induces autophagy and modulates the antitumor activity by lowering Mcl-1 levels in OSCC cells

SCC2095

[89]

α-l-Diginoside cardiac glycosides

Strophanthus divaricatus (Apocynaceae)

α-l-Diginoside treatment inhibited cellular proliferation. It inhibited Mcl-1 via proteasomal degradation. Additionally, it modulates Jak/Stat signaling

SCC2095, SCC4

[113]

Manumycin A (Manu A) natural antibiotic

Streptomyces parvulus

Manumycin A treatment resulted in Sp1 mediated apoptosis. It reduced Sp1 protein levels, thereby modulating its downstream targets like increasing p27 and p21, and decreasing Mcl-1 and survivin

HN22, HSC4

[81]

Guggulsterone phytosteroid

Commiphora mukkul

Guggulsterone treatment led to effective cytotoxic activity by inducing apoptosis in chemoresistant cancer cells. It targets 14-3-3 zeta to initiate apoptosis through the intrinsic mitochondrial pathway by releasing Bad from its inhibitory action. Additionally, it suppressed the expression of anti-apoptotic proteins xIAP, Mcl-1, c-myc, and survivin in SCC4 cells

SCC4, HSC2

[72]

Wogonin flavonoid

Scutellaria baicalensis Georgi

Wogonin treatment had significant cytotoxic effects. It targets the Nrf2-ARE pathway associated with chemotherapeutic resistance along with Mcl-1. Additionally, it induces intracellular ROS accumulation and GSH depletion. This leads to the potentiation of cisplatin cytotoxicity

AMC-HN4-cisR, HN9-cisR

[90]

Cyclocommunol (CYC) prenylflavonoid

Artocarpus altilis

CYC treatment caused pro-apoptotic effects via down-regulating the phosphorylation/expression of Akt/mTOR and Mcl-1

SCC2095, Ca922

[91]

Furano-1,2-naphthoquinone (FNQ) iNOS inhibitor

Avicennia marina

FNQ treatment led to cellular apoptosis via upregulation of Bax, Bad, and downregulation of Bcl-2, Bcl-xL, Mcl-1, and XIAP, resulting in cytochrome C release and sequential activation of caspase-9 and caspase-3. Additionally, it inactivated Src and PI3K/Akt-mediated cell signaling, which led to cell cycle arrest

Ca9-22, SAS,

CAL27

[73]

Cardiotoxin III

Naja naja atra

Cardiotoxin III treatment abrogated the activation of EGFR and downstream events including phosphorylation of STAT3, STAT5, Akt, and ERK1/2. Moreover, it upregulated Bax expression and downregulated Bcl-2, Bcl-xL, and Mcl-1 expression

Ca9-22

[114]

Water extract of Sanguisorba officinalis

Sanguisorba officinalis

HESO treatment led to reduced cell growth and induced apoptosis in HSCC4 and HN22. In the HSC4 cell line, HESO reduced Mcl-1, which led to the activation and oligomerization of Bak, whereas in the HN22 cell line, HESO decreased Sp1 and its downstream target, survivin.

HSC4, HN22

[82]

Methanol extract of C. officinale Makino and C. bursa‑pastoris

C. officinale Makino

C. bursapastoris

MECO and MECB treatment led to a reduction in cellular viability. It led to downregulation in Sp1 levels. Mcl-1 was down-regulated as a downstream target for Sp1

HSC2

[83]

Methanol extract of Dianthus chinensis and Acalypha australis

Dianthus chinensis and Acalypha australis

MEDC and MEAL treatment led to a reduction in cellular viability. It led to downregulation in Sp1 levels. Mcl-1 was down-regulated as a downstream target for Sp1

YD15, SCC15

[84]

Bitter melon

Momordica charantia

BME treatment led to inhibition in cellular proliferation. The treatment led to the inhibition and downregulation of c-met and its downstream targets, such as phospho-STAT3 (Tyr705) and Mcl-1 (long anti-apoptotic form). Additionally, a reduction in c-myc was also observed.

Cal27 (tongue),

JHU-22 (Larynx),

JHU-29(tongue)

[71]

Methanol extract

of Convallaria keiskei

Convallaria keiskei

MECK treatment led to increased cell death. It induced Mcl-1 downregulation in a translation-dependent manner. Mcl-1 downregulation resulted in truncated Bid-induced mitochondrial apoptosis and downregulation in ERK1/2 phosphorylation

MC3, HN22

[74]

Lycorine hydrochloride

Lycoris radiate

Lycorine hydrochloride treatment inhibited the proliferation of OSCC cells. It induces the mitochondrial pathway and is involved in ROS-mediated apoptosis. It upregulated the expression levels of the pro-apoptotic members, Bax and Bim, but down-regulated the expression of the anti-apoptotic protein, Mcl-1, in a dose-dependent manner

HSC3

[75]

Ethanolic extract

of Juniperus squamata

Juniperus squamata

EEJS treatment had cytotoxic effects on OSCC cells. It induced mitotic catastrophe, which led to apoptosis, via Mcl-1 reduction

HSC3, HSC4

[76]