Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?

Abstract

Certain subtypes of cancer cells require oxidative phosphorylation (OXPHOS) to survive. Increased OXPHOS dependency is frequently a hallmark of cancer stem cells and cells resistant to chemotherapy and targeted therapies. Suppressing the OXPHOS function might also influence the tumor microenvironment by alleviating hypoxia and improving the antitumor immune response. Thus, targeting OXPHOS is a promising strategy to treat various cancers. A growing arsenal of therapeutic agents is under development to inhibit this biological process. This Perspective provides an overview of the structure and function of OXPHOS complexes, their biological functions in cancer, relevant research tools and models, as well as the limitations of OXPHOS as drug targets. We also focus on the current development status of OXPHOS inhibitors and potential therapeutic strategies to strengthen their clinical applications.

Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15

“…Tumor metabolism and energy reprogramming has recently regained traction as a critical area of focus in cancer research [ 30 ]. Cancer cells often exhibit altered mitochondrial function, including mitochondrial DNA mutations, augmented energy metabolism, elevated reactive oxygen species (ROS) generation, and increased mitochondrial membrane potential [ 31 , 32 ]. The term “Mitocans” encompasses the broad range of anti-cancer agents that act via cancer cell mitochondrial destabilization, and uncouplers of oxidative phosphorylation have recently been included as promising new agents [ 33 ].…”

A Family of Glycosylated Macrolides Selectively Target Energetic Vulnerabilities in Leukemia

“…The assay readout consisted of 5 mM glucose, 2.5 U/ml hexokinase (Sigma H4502), 2.5 U/ml glucose-6-phosphate dehydrogenase (Sigma G8529), and 1.6 mM NADP + (Sigma N8035). 20 μM P 1 ,P 5 -di(adenosine-5) pentaphosphate (AP5A) was used to inhibit adenylate kinase which could otherwise convert 2 ADP → AMP + ATP. The assay reagents were prepared at 2 × in RB and 100 μL was dispensed into each well of UV transparent 96 well plate.…”

“…Alterations in bioenergetics have long been recognized as a hallmark of cancer 2–4 , with Warburg’s observation that some cancer cells convert glucose to lactate in the presence of adequate oxygen – aerobic metabolism. Although Warburg metabolism predominates in many cancers, there is increasing recognition that some cancers and subsets of cancer cells are dependent on mitochondrial oxidative phosphorylation (OXPHOS) to serve both bioenergetic and biosynthetic needs 5–7 . Notably, OXPHOS dependence appears to be a recurrent vulnerability of cancer stem cells (CSCs) and leukemia stem cells (LSCs), which are often responsible for treatment failure 8–11 .…”

Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects

“…The hydroxyl group ( -OH in HU) is thought to be critical for its antiproliferative and antitumor mechanisms (Madaan et al, 2012;Singh and Xu, 2016). In this study, we modified the structure Increasing evidence suggests that certain subtypes of cancer cells, including cancer stem cells and chemotherapy-resistant cancer cells, utilize oxidative phosphorylation (OXPHOS) to obtain the energy needed for survival and proliferation (Fiorillo et al, 2016;Xu et al, 2020). Targeting OXPHOS, especially mitochondrial complex I, is emerging as a potential antitumor strategy to treat several types of cancer (Cheng et al, 2013(Cheng et al, , 2016(Cheng et al, , 2019Boyle et al, 2018;Weinberg and Chandel, 2015;Xu et al, 2020;Fischer et al, 2019;Pan et al, 2018).…”

“…As previously suggested (American Association for Cancer Research, 2019), OXPHOS inhibitors that target cancer cells will also target cancer-associated immune cells. Reports suggest that suppression of OXPHOS function in cancer cells could influence the tumor microenvironment (TME) by inhibiting hypoxia and enhancing the antitumor response (Xu et al, 2020). However, to our knowledge, mitochondria-targeted derivatives with varying hydrophobicities on cytotoxic and tumor suppressive cells in the TME have not been thoroughly tested.…”