Table 1 The chemotherapeutic agents which may cause resistance due to CSCs, and the overview of the pathogenic mechanism of quiescence or enhanced stemness.

Sorafenib

HCC

1. Upon mTORC1 inhibition through sorafenib treatment, elevated laminin-332 expression was observed to broadly decrease cell mitosis, indicating a quiescent state of CSCs;

2. the development of HCC in a microenvironment enriched with ECM proteins, including laminin-332, ultimately led to sorafenib-resistant HCC, dependent on the α3β1/Ln-332 axis;

3. the HIF1α/USP22 positive feedback loop in promoting glycolysis and stemness on TP53 inactivation, which is known to control the balance between quiescence and proliferation in CSCs, in sorafenib-resistance HCC.

1. Ungiven;

2. Ungiven;

3. 2-DG.

[49, 59, 57]

5-fluorouracil

1. Colon cancer

2. HCC

1. Quiescent CSCs expressed increased levels of ZEB2 and further upregulated pCRAF/pASK1 levels resulting in increased chemoresistance;

2. 5-FU inhibits CD90⁺ proliferating CSCs, some of which produce CD13⁺ semiquiescent CSCs, while CD13 inhibition suppresses the self-renewing and tumor-initiating ability of quiescent CSCs.

1. Ungiven;

2. combining a CD13 inhibitor with a ROS-inducing chemo/radiation therapy

[19, 109]

Cytarabine

Acute myeloid leukemia

1. Quiescent leukemia stem cells (LSCs) expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML;

2. c-MPL-positive cell population within Lin⁻ c-Kit⁺ leukemia cells included a high percentage of LSCs in a quiescent state, enhanced colony formation ability, and increased homing efficiency.

1. a novel EZH1/2 dual inhibitor to sensitize LSC to the cytarabine;

2. AMM2, a c‐MPL inhibitor to sensitize LSC to the cytarabine.

[102, 104]

Cisplatin

Breast cancer

1. MDA-MB-231PAC10 cells are quiescent with a delayed doubling time, which may be caused by the high expression of p21(Waf1).

1. Disulfiram inhibits CSC marker expression and reverses paclitaxel and cisplatin resistance in cells.

[105]

BCR-ABL1 targeted tyrosine kinase inhibitor

CML

1. GLI2 expression enhances leukemic progenitor dormancy in stromal co-cultures.

1. SMO inhibition, a clinical antagonist of GLI2, can sensitize LSCs to TKI in vivo at doses manner.

[106]

EGFR TKIs including gefitinb, erlotinib, osimertinib

1. Lung cancer

2. Osteosarcoma cancer

3. Cholangiocarcinoma

1. Culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs

2. TGFβ-miR-499a-SHKBP1 network orchestrates the EMT kinase switch that induces resistance to EGFR inhibitors in CD166⁺ OSCs;

3. In vivo, tumors developed from resistant cholangiocarcinoma cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF).

1. Ungiven.

2. Ungiven.

3. Ungiven.

[56, 65, 67]

Docetaxel

Breast cancer

1. CD10 + GPR77 + CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation. CD10 + GPR77 + CAFs promote successful engraftment of patient-derived xenografts, and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor sensitivity.

The neutralizing anti-GPR77

[62]

Oxaliplatin

Colorectal cancer

1. H19 was enriched in CAF-derived conditioned medium and exosomes, which in turn promoted the stemness of CSCs and the chemoresistance of CRC cells in vitro and in vivo.

1. Ungiven.

[66]

Gemcitabine

Pancreas cancer

1. Inhibition of glycolysis using 2-deoxy-D-glucose (2-DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo.

1. Ungiven.

[88]