Die-hard survivors: heterogeneity in apoptotic thresholds may underlie chemoresistance

Abstract

The unmatched efficacy of microtubule-targeting agents (MTAs) as chemotherapeutics was once assumed to originate from their impact on mitotic processes; however, this misconception is being eroded by amassing data that MTAs instead target interphase functions in patients’ tumors. What remains murky is how MTAs target malignant cells over non-malignant ones if proliferation rates do not distinguish them. In many instances, malignant cells are actually more ‘primed’ for apoptosis than non-malignant ones. Nevertheless, even if most cells within the tumor are more apoptosis-susceptible than those in healthy tissues, there likely exist small subpopulations of apoptosis-resistant clones that engender incomplete responses to MTAs and relapse. Therefore, intratumor heterogeneity in terms of proximity to the apoptotic threshold must be better understood to facilitate the design of chemotherapeutic regimens, which may benefit from including drugs like BH3 mimetics that help in lowering the apoptotic threshold of tumor cells within these chemoresistant subpopulations.

Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells

“…CPT-11 or its metabolic product SN-38 possibly intervenes in apoptosis-associated pathways, influencing the expression of Bax, Bcl-2 and cleaved-caspase-3 in LoVo/CPT-11 CSCs. However, on account of the active DNA repair mechanisms, high expression of ABC transporters, and resistance to apoptosis in CSCs, the function and morphology of plasma membrane and nucleus may not change (18,52).…”

TGF‐β receptor I inhibitor enhances response to enzalutamide in a pre‐clinical model of advanced prostate cancer

“…The present study defines for the first time the consequences of inhibition of TGF‐β signaling on regulators of two dynamic processes, EMT interconversion to MET and the actin cytoskeleton organization, leading to re‐differentiation of prostate tumors in an in vivo model. Heterogeneity in apoptotic thresholds may underlie therapeutic resistance and TGF‐β causes tumor suppression via a lethal EMT programing . The events of dramatic cofilin depletion (compromising the integrity of cytoskeleton) and phenotypic changes (promoting MET) may drive an enhanced response to the combination strategy of galunisertib and the antiandrogen in advanced tumors.…”

“…Although TGF‐β‐induced EMT in prostate tumorigenesis can be compromised via effects of the AR axis on TGF‐β effectors SMADs 3, 4, that negatively regulate AR‐transcription, in our study we found that inhibition of TGF‐β signaling has no effect on nuclear AR. Since Smad4 translocates to the nucleus in response to TGF‐β by binding to Importin 7/8, the effect of TGF‐β blockade on the association of Importin7 and Smad4 in prostate tumor cells is being examined …”

MiR-1268b confers chemosensitivity in breast cancer by targeting ERBB2-mediated PI3K-AKT pathway

“…Then, we showed that miR-1268b overexpression promoted cells apoptosis and sensitized chemosensitivity to adriamycin in breast cancer. The main mechanism of chemotherapeutic drugs exerting their anticancer effects is to induce apoptosis [ 30 ]. To further verify the relationship of miR-1268b and chemosensitivity of breast cancer, we performed cell drug sensitivity experiments, and the results demonstrated that miR-1268b could increase the sensitivity of MCF-7/ADM to adriamycin, as well as the apoptosis of breast cancer cells.…”