Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Abstract

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.

Carrier-Free Nanoplatform via Evoking Pyroptosis and Immune Response against Breast Cancer

“…Strikingly, the immunoblot and LDH release assay results of laser irradiation could be significantly rescued by NAC (Figures S6B,D and S8D–E), suggesting that ROS was the driving element to induce cell pyroptosis. All of the results elucidated the underlying mechanism that the A-C/NPs triggered ROS generation under NIR laser irradiation to induce pyroptosis through damaging the homeostasis of the mitochondrial pathway, thus exhibiting satisfactory antitumor potential in vitro .…”

DLDH-containing extracellular vesicles from CAFs reduced DOX sensitivity in triple-negative breast cancer

“…3D, E). Recent evidence suggests that the metabolic pattern is crucial for chemo-resistance in cancers [22]. As a rate-limiting enzyme, α-KGDC activity may induce alterations in the ux of metabolites through TCA.…”

“…α-KGDC represents a major modulator of ETC activity and TCA cycle ux, and is a pivotal enzyme in the metabolic reprogramming [20], and its activation suppressed via the hypoxia-inducible factor 1 (HIF1) could impede tumor growth in vivo [21]. DLDH, as its E3 subunit, is involved in the decarboxylation of pyruvate to form acetyl-CoA and reduced NAD to NADH during the cascade of glucose metabolism and mitochondrial ATP production [18,22]. Our study revealed that EVs-DLDH was delivered and enriched in the mitochondria of the recipient cells, promoting the activity of α-KGDC and NADH production (Fig.…”

Drug Resistance in Cancers: A Free Pass for Bullying

“…Importantly, it is well reported that apoptotic cell death is mediated by autophagy, which occurs prior to apoptosis in chemosensitive tumor cells but not in chemoresistant tumor cells since mitochondrial remodeling has been confirmed [ 219 ]. Typically, autophagy induced by mitochondrial remodeling often causes treatment failure that is associated with drug resistance to common chemotherapeutic drugs including CDDP, DOX, 5-FU, and PTX [ 220 ].…”