Known and investigational anti-cancer drugs with potential to target 3Cs
| Drugs | Effect on CIN | Effect on cancer immunity | CSCs | References |
|---|---|---|---|---|
| Chemotherapeutics drugs | ||||
| 5-Fluorouracil | ↓ DNA and RNA synthesis | ↑ Tumor-infiltrating CTLs | Suppress CSC in the PANC-1 cell line by inhibiting p38 | [121, 122] |
| Cyclophosphamide | ↓ DNA replication process | ↑ NK and T cell activity; ↓ Treg activity | CSCs found to be resistant to cyclophosphamide | [123, 124] |
| Doxorubicin | Perturbation of replication and transcription | ↓ Activation of the immune system | Co-delivery of all-trans-retinoic acid and doxorubicin inhibit CSCs | [125–127] |
| Gemcitabine plus cisplatin | ↓ DNA and RNA synthesis | ↓ Circulating Treg cells | Cisplatin and plasma-activated medium cause death of CSC | [128, 129] |
| Paclitaxel | ↓ Mitosis | ↑ CD68+ macrophage, NK, and CTL tumor invasion | Paclitaxel and sorafenib combination suppressed self-renewal of CSCs | [130–132] |
| Immunotherapeutics drugs | ||||
| Vemurafenib | Inhibit BRAFV600E | ↑ gp100, MART1, and other antigen expressions ↓ Immune-suppressive cytokine secretion | ↓ CSC traits | [133, 134] |
| Temsirolimus, rapamycin, and other mTOR inhibitors | Targets mTOR pathway | ↑ CD8+ T-cell activation, IFN production, and differentiation into memory cells; ↓ IDO expression by Treg homeostasis. ↑ Treg response to antigen | Can lead to preferential apoptosis of CSCs | [135, 136] |
| PI3K-AKT inhibitors | ↓ PI3K-AKT mediated signaling in malignant cells | ↑ The ability of CTLs and NK cells to lyse tumors using perforin-granzyme; ↓ pro-survival signaling, and pro-tumor inflammation | Rottlerin-induced apoptosis of CSC by inhibiting the PI3K-AKT-mTOR pathway | [137–139] |
| Imatinib | Targets multiple tumor-linked tyrosine kinases, like ABL and cKIT | Targets IDO, ↓ efficiency, and number of Treg cells; ↑ DC-NK cell cross-talk | Conflicting data | [140, 141] |
| CSC targeting drugs | ||||
| Paclitaxel + reparixin | ↓ Mitosis | NK and CTL tumor invasion | Targets CSC in triple-negative breast cancer | [142] |
| GDC-0449 + conventional therapy | ↓ Hh signaling in pancreatic cancer | Not reported yet | Targets CSC (phase II) | [142] |
| CAR-T EpCAM | Targets EMT | Improve infiltration of T-cells with Wnt inhibitor | Targets CSC (phase I/II) | [10, 143] |
IDO: indolamine 2,3-dioxygenase; MART1: melanoma antigen recognized by T cells; mTOR: mammalian target of rapamycin; cKIT: type III receptor tyrosine kinase. ↓: inhibition or decrease; ↑: activation or increase
