Drug and apoptosis resistance in cancer stem cells (CSCs): A puzzle with many pieces

Abstract

Resistance to anti-cancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anti-cancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal (EMT) progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment (TME) creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), Bcl-2 family members, inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

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“…Apoptosis is remarkably deregulated in cancer, displaying a hallmark of immortality and uncontrolled proliferation. 73,74 Cells undergoing apoptosis shrink, show cell membranes blebbing, DNA fragmented, cytoskeleton degraded, and phagocytosis signaled. 74,75 Tumor cells send various factors into the surrounding microenvironment to repress programmed cell death.…”

Unravelling the role of Silibinin in targeting CD44+ cancer stem cells: Therapeutic implications, effective strategies and approaches

“…Apoptosis resistance is one of the common mechanisms which enables the malignant cells to survive chemo‐therapeutic treatment and allows prolonged tumour growth (Safa, 2022). Furthermore, evidence suggests that treating Silibinin decreases antiapoptotic protein Bcl‐2 expression in pancreatic and colon CSCs whilst simultaneously increasing pro‐apoptotic protein Bax expression and activating the mitochondrial pathway of apoptosis (Khakinezhad Tehrani et al, 2020; Sameri et al, 2021).…”

“…Subsequently, there was an increased population in the sub-G0 cell cycle phase, which may substantiate an initiation of malignant cells' apoptotic cell death pathway. Silibinin exhibits the potential to modulate different cell cycle phases to impede abnormal cellular proliferation.Apoptosis resistance is one of the common mechanisms which enables the malignant cells to survive chemo-therapeutic treatment and allows prolonged tumour growth(Safa, 2022). Furthermore, evidence suggests that treating Silibinin decreases antiapoptotic protein Bcl-2 expression in pancreatic and colon CSCs whilst simultaneously increasing pro-apoptotic protein Bax expression and activating the mitochondrial pathway of apoptosis(Khakinezhad Tehrani et al, 2020;Sameri et al, 2021).…”

Update on immune‐based therapy strategies targeting cancer stem cells

“…C‐FLIP is considered a critical regulator of the death receptor (DR) networks and is a catalytically inactive caspase‐8/‐10 homolog. c‐FLIP protein significantly induces anti‐apoptotic activities through inhibiting cytokine‐ and chemotherapy‐mediated apoptosis, which results in resistance to these agents 81 . Therefore, targeting drug resistance to increase the sensitivity of CSCs to chemotherapeutic substances or radiotherapy administration could be a promising approach.…”