Table 4 Therapeutic strategy targeting Mcl-1 in oral cancer (synthetic)

Bcl-2 inhibitor

Obatoclax

(GX15-070)

Obatoclax inhibited Mcl-1. The treatment led to the induction of HNSCC cell apoptosis in a Mcl-1-dependent manner. Its cytotoxicity increased following synergism with chloroquine (autophagy inducer)

UMSCC-1, Cal33

[46]

ABT-737

ABT-737 alone or in combination with radiation led to repression of cellular Mcl-1 via Noxa upregulation. The combination between ABT 737 and radiation had a synergistic effect when compared with ABT 737 alone

SQ20B, SCC61,

Cal27, Cal33

[47]

Sabutoclax

OSCC cell survival was dependent on Mcl-1. Silencing Mcl-1 led to ABT 737-dependent cell death. Sabutoclax induced cancer-specific cell death in a Mcl-1-dependent manner. It also led to the induction of autophagy. Sabutoclax inhibited tumor growth in vivo. The effects were enhanced when used with celecoxib

H357, SCC-4, SCC-9, FaDu, In Vivo

[97]

TW-37

(BH3 mimetic)

TW-37 induced apoptosis in OSCC cells by suppressing STAT3–Mcl-1 signaling. It also enhanced the effects of cryptotanshinone

HSC-3, Ca9.22, HSC-4

[48]

Proteasome inhibitor

MG132

MG132 sensitized HNSCC cells to apoptotic cell death mediated by DR5/DR4 ligand TRAIL or agonistic DR4 monoclonal antibody AY4. It inhibited the interaction of Bak with Mcl-1 and Bcl-xL via Bik

HN3, HN6

[49]

Carfilzomib/IV ONX0912 (oprozomib)

Obatoclax inhibited Mcl-1. The treatment led to the induction of HNSCC cell apoptosis in Mcl-1-dependent manner. Its cytotoxicity increased following synergism with chloroquine (autophagy inducer)

UMSCC22A, 1483,

UMSCC22B, UMSCC-1

[98]

Kinase inhibitor

Alisertib

(MLN8237)

Aurora-A kinase inhibitor (Alisertib) led to degradation of Mcl-1 in HPV E7-expressing HNC cells. Cotreating with MG132 rescued Mcl-1 expression

SCC90, SCC104, SCC25

[50]

Sorafenib

Sorafenib leads to proteasomal degradation of Mcl-1 and inhibition of translation. It can induce apoptosis through a STAT3/Mcl-1/t-Bid signaling pathway

MC3, YD15

[51]

AZD-1775

(Wee-1 inhibitor)

AZD-1775 decreased the expression of the anti-apoptotic proteins, Mcl-1 and XIAP, by increasing the sensitivity of HPV + HNSCC cells to cisplatin

HPV16 + HNSCC cells,

UMSCC47, HMS-001,

HPV16- HNSCC cells, HN30(wtp53), HN31(mutp53),

In vivo

[99]

EGFR inhibitor

Afatinib

Afatinib stimulates the PERK–eIF2α–ATF4 axis, which contributes to MCL-1 downregulation and subsequent apoptosis via suppressing Akt–mTOR signaling

FaDu, Detroit562,

HN6, CAL-27

[53]

SKLB188

SKLB188 induced caspase-dependent apoptosis by down-regulating Mcl-1 and survivin. It primarily inhibits the EGFR signaling

FaDu, PCI-13, In vivo

[52]

RNA synthesis inhibitor

Mithramycin A

Mithramycin A treatment led to the downregulation of Mcl-1. Mcl-1 inhibition led to an increase in pro-apoptotic protein Bax, resulting in the Bax translocation into mitochondria and its oligomerization

HN22, HSC4, In vivo

[33]

HDAC inhibitor

Panobinostat (LBH589)

Panobinostat treatment led to suppression of Sp1 protein, which led to Mcl-1, cyclin D1, and survivin. It also upregulated the expression levels of p27 and p21

HN22, HSC4

[54]

Splicing factor 3B1 inhibitor

Meayamycin B

Meayamycin B inhibited SF3B, which led to a reduction in anti-apoptotic Mcl-1 L isoform by modulating splicing of Mcl-1 mRNA. Stronger toxicity was seen in Mcl-1 abundant and HPV16 negative HNSCC cells

HPV + UD-SSC2, UM-SCC47, 93-VU-147T,

UPCI: SCC90,

HPV- PCI-13,

PCI-15B, UM-SCC22B

[55]

Survivin inhibitor

Sepantronium bromide (YM155)

YM155 inhibited survivin, Sp1, and Mcl-1. Survivin and Mcl1 were inhibited via lysosomal-dependent degradation. Moreover, Sp1 inhibition also led to downregulation of Mcl-1

MC3, HN22

[56]

Antisense Oligonucleotides

Mcl-1 antisense oligonucleotides

Mcl-1 antisense oligonucleotides led to a significant reduction in Mcl-1 protein. Additionally, a synergistic cytotoxic effect was observed with cisplatin, 5-fluorouracil (5-FU), gemcitabine, paclitaxel, or cetuximab

SCC9

[100]

Acetylsalicylic acid (ASA)

Aspirin

Aspirin led to the downregulation of the Mcl-1 protein. Mcl-1 proteolysis was caspase dependent

YD8

[57]

Aspirin + Sorafenib

Aspirin with sorafenib treatment had a synergistic impact on the induction of cell death. The combination treatment induces xCT inhibition, GSH depletion, and ROS accumulation. In addition, the combination of aspirin and sorafenib induced c-PARP and decreased p65, Mcl-1, and xCT protein expression

HN2-10, In vivo

[101]

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Tolfenamic acid

Tolfenamic acid treatment led to inhibition of proliferation in cancer cells. It led to a reduction in Mcl-1 at both protein and mRNA levels via Sp1

YD15

[79]

Immunosuppressant

FTY720

FTY720 induced downregulation of Akt/NF-κB pathway, ROS generation, Mcl-1 degradation, and autophagy-dependent apoptosis in OSCC cells.

SCC2095

[58]

Chemotherapy medication

Vincristine

Vincristine treatment induces HMGB1 release leading to autophagy, which protects oral cancer cells. HMGB1 increases Mcl-1 expression via RAGE signaling and protects the cells from vincristine-induced apoptosis

SCC9, OECM-1

[102]

Fenretinide +

ABT-263

Fenretinide treatment along with ABT-263 significantly induced apoptosis. MCL-1 and BCL-xL are the primary targets of apoptosis induced by ABT-263 in combination with Ad-Noxa or fenretinide

HN8, HN12, HN30, UMSCC1, UMSCC47, UMSCC104

[64]

C6 ceramide + PKC412

C6 ceramide co-treatment significantly augmented PKC412-induced lethality in HNSCC cells. Together they synergistically decreased Akt–mTOR activation. C6 ceramide sensitized the cells to PKC412 via down-regulating Mcl-1.

SQ20B, SCC-9

[65]

Antipsychotic drug

Thioridazine + curcumin

Thioridazine and curcumin combined treatment induced apoptosis through down-regulating c-FLIP and Mcl-1 expression at the post-translational levels via NOX4-mediated upregulation of proteasome activity

AMC-HN4

[66]

Thioridazine + carboplatin

Thioridazine plus carboplatin induces apoptosis in human head and neck cancer cells. The augmentation of proteasome activity by mitochondrial ROS-mediated PSMA5 expression induced the downregulation of c-FLIP and Mcl-1 expression in thioridazine plus carboplatin-treated cells

AMC-HN4

[103]

Anesthesia

Propofol

Propofol treatment led to the induction of apoptosis via inducing GAS5 via FoxO1. GAS5 down-regulates mir-1297 which suppresses GSK3β. This led to a significant reduction of Mcl-1.

UM-SCC6, SCC090

[59]

Biochemical synthetic product

Glucosamine hydrochloride

(GS-HCl)

GS-HCl significantly reduced proliferation and induced apoptosis. It transcriptionally repressed Mcl-1 and HIF-1α in a concentration-dependent manner. Additionally, it also led to the mitochondrial-dependent activation of caspases and triggered ER stress

YD-8

[62]

Fucoidan

Fucoidan treatment significantly induces apoptotic cell death by inactivating the ERK1/2 pathway thereby regulating the Mcl-1 protein

MC3

[63]

Naphtho[1,2-b]

furan-4,5-dione

NFD treatment led reduction in cancer cell growth. It led to the phosphorylation of EGFR. This led to a reduction in phosphorylation of PI3K and Akt. Dysregulation in PI3K and Akt led to a reduction in Mcl-1. Additionally, it led to downregulation of NF-κB and phosphorylation of IκKβ.

Ca9-22, SAS, CAL27

[60]

Triptolide

Triptolide treatment led to the inhibition of Mcl-1 mRNA levels. It synergistically enhanced chemotherapy-induced cell death in chemoresistant OSCC

H357, SCC4

[38]

Anti-malaria &semi-synthetic product

Dihydroartemisinin

Dihydroartemisinin treatment induced antitumor effects. The antitumor effects were due to the inhibition of STAT3 via Jak2 kinase. The downstream targets of STAT3 including Mcl-1, Bcl-xL, Cyclin-D1, and VEGF were down-regulated

FaDu, Cal-27, In Vivo

[61]