Table 5 Progress in drugs targeting CSC transcription——From cell experiments, animal models to clinical trials
Drug name | Target | Mechanism | Condition | Stage | Usage | Outcome |
|---|---|---|---|---|---|---|
Ursolic acid | C-MYC | Increases PTEN expression to inactivate the FAK/PI3K/AKT/mTOR signaling pathway | Breast cancer | Experimental Study in vitro | Alone | Reduce the proportion of CSC and inhibit the migration and invasion of breast cancer [214] |
Pongol methyl ether | OCT4, NANOG | Combine with AKT-1 to reduce signal transduction | Primary lung cancer | Experimental Study in vitro | Alone | Suppress spheroid formation and reduce CSC-specific marker expression [215] |
Flavonoids (Nobiletin and Xanthohumol) | Wnt pathway | Reduce the activation of the Wnt pathway and down-regulate the expression of CD44 | CRC | Experimental Study in vitro | In combination with 5-fluorouracil and oxaliplatin | Decrease stemness properties of CSCs and sensitize CSCs to standard chemotherapy [216] |
MHY1485 | mTOR pathway | Stimulate mTOR pathway and inhibit autophagy | Esophageal cancer | Experimental Study in vitro | Alone | Reduce CSC population and cancer stemness [217] |
Atractylenolide I | PI3K/AKT/mTOR pathway | Inhibit the uptake of extracellular vesicles carrying miR-200c to influence signal pathway | CRC | Experimental Study in vitro | Alone | Obstruct the metastasis of CRC [218] |
Thiamine tetrahydrofurfuryl disulfide | SOX2, OCT4 and NANOG | Inhibit the expression of stem gene | ESCC | Experimental Study in vitro and vivo | In combination with cisplatin/ concurrent chemoradiation therapy (CCRT) | Diminish stemness and enhance CCRT efficacy [219] |
α-Mangostin | SOX2, OCT4 and NANOG | Induce mitochondrial apoptosis | Cervical carcinoma | Experimental Study in vitro and vivo | Monotherapy or in combination with Cisplatin | Synergically enhanced the cytotoxicity of cisplatin on CSC and reduce the stemness and proliferation of CSC [220] |
A targeted co-delivery nanosystem of Salinomycin and doxorubicin | OCT4, NANOG | Redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety down-regulate stem gene | Breast cancer | Experimental Study in vitro and vivo | Combination therapy | Reduce the risk of tumor metastasis and effectively alleviate splenomegaly caused by malignant tumors [221] |
Sulforaphane | SOX2, OCT4, Notch, SMO and GLI | Inhibit the expression of CSC related stem gene | HNSCC | Experimental Study in vitro and vivo | In combination with Cisplatin or 5-fluorouracil | Inhibit CSC colony and tumor progression, enhance chemotherapeutics cytotoxicities against CSCs [222] |
Rosiglitazone | SOX9, SOX2, OCT4 and NANOG | Up-regulate ETS homologous factor (EHF) to inhibit transcription | PDAC | Preclinical experiments in mice | Monotherapy | Inhibit cancer stemness, suppress the crosstalk between PDAC and CSCs, sensitise PDAC to gemcitabine therapy [223] |
Glucosamine-labeled liposomal ceramide | OCT4, SOX2, CD44 and CD133 | Target HIF-1α to block gene transcription | Lung cancer | Preclinical experiments in mice | In combination with paclitaxel and carboplatin | Three quarters of mice have a high tumor clearance rate [224] |
Wortmannin | SOX2, OCT4 and NANOG | Inhibit PI3K/AKT/TBX3 signal transduction to down-regulate the expression of pluripotent gene | HCC | Preclinical experiments in mice | Monotherapy or in combination with Sorafenib | Reduce tumor size and weight [225] |
Stattic | OCT4 | Block STAT3 phosphorylation and activation, thereby reducing the expression of CCL16 to target the Wnt pathway | Breast cancer | Preclinical experiments in mice | Monotherapy | Inhibit tumor growth and decrease tumor volume [226] |
PTC596 | BMI-1, OCT4 | Directly hinder the expression of BMI-1 | Adenoid cystic carcinoma (ACC) | Preclinical experiments in mice | Monotherapy or in combination with Cisplatin | decrease the CSC fraction in tumors and prevent tumor relapse for 150Â days [227] |
SNS-032 | KLF4, C-MYC | Inhibit cyclin dependent kinase 7/9 to obstruct transcription | Uveal melanoma | Preclinical experiments in mice | Monotherapy | Induce CSC elimination and reduce liver metastasis in tumor [228] |
NHWD-870 | C-MYC, HIF-1α, TAM | Inhibit BRD4 to target HIF-1α, hinder the expression of C-MYC and block the proliferation of TAM | Solid tumors and hematological malignancies | Preclinical experiments in mice | Monotherapy | Show strong anti-tumor activities in nine mouse models [229] |
Emodin | TGF-β pathway | Block TGF-β signal transduction to inhibit pluripotent TF and act on TAM | Breast cancer | Preclinical experiments in mice | Monotherapy | Inhibit postoperative lung metastasis and significantly increase the survival [230] |
INCB057643 | MYC | Target BET to hinder the transcription of MYC | Advanced malignancies | Phase I/II clinical trial | Monotherapy or in combination with standard-of-care | Possess targeted toxicity and limited anti-tumor activity [231] |
BMS-986158 | MYC | Target BET to hinder the transcription of MYC | Advanced malignancies | Phase I/IIa clinical trial | Monotherapy | Yield tolerable safety and preliminary antitumor activity [232] |
Nirogacestat | Notch pathway | Inhibit γ secretory enzymes | Desmoid Tumor | Phase III clinical trial | Monotherapy | Show significant benefits in various aspects [233] |
CB-103 | Notch pathway | Selectively inhibits the CSL-NICD interaction | ACC and hematologic malignancies | Phase I clinical trial | Monotherapy | Possess controllable safety and biological activity, but limited clinical anti-tumor activity [234] |
Sonidegib | Hh pathway | Combine and inhibit SMO | Basal cell carcinoma | Phase II clinical trial | Monotherapy | Demonstrate sustained efficacy and a manageable safety profile [235] |
Sonidegib | Hh pathway | Combine and inhibit SMO | Myeloid neoplasms | Phase I clinical trial | In combination with azacitidine | Confirm the safety of the combination but yield limited response rate in patients [236] |
Napabucasin | STAT3 | Directly inhibit gene transcription driven by STAT3 | Metastatic colorectal cancer | Phase I/II clinical trial | In combination with pembrolizumab | Indicate antitumor activity with acceptable toxicities [237] |
Decitabine | DNMT | Inhibit DNMT to lead to DNA hypomethylation and alter gene expression | Acute myeloid leukaemia | Phase II clinical trial | In combination with venetoclax | Show a manageable safety profile and high activity, need future larger and randomised studies [238] |
Chidamide | HDAC, Notch1, MYC | Inhibit HDAC and down-regulate the level of the intracellular form of Notch1 and MYC | Angioimmunoblastic T-cell lymphoma | Phase II clinical trial | In combination with prednisone, etoposide, and thalidomide | Display effectiveness, tolerability, and economy [239] |
Chidamide | HDAC, Notch1, MYC | Inhibit HDAC and down-regulate the level of the intracellular form of Notch1 and MYC | Advanced, hormone receptor-positive breast cancer | Phase III clinical trial | In combination with exemestane | Improve progression-free survival compared with placebo plus exemestane [240] |