Indirect inhibitors of cellular respiration for the treatment of glioblastoma

A new research perspective has been published in Oncotarget.com Volume 14 dated May 4, 2023, “Targeting cellular respiration as a therapeutic strategy in glioblastoma.”

While glycolysis is abundant in malignancies, mitochondrial metabolism is also important. Mitochondria contain enzymes related to cellular respiration, which is a pathway critical to both the replenishment of reducing equivalents and the production of energy in the form of ATP.

In this research perspective, researchers Inyuan Chang, Trang Thi Thu Nguyen, Mike Andrew Westhoff, George Karbel Massler, And Marcus D From Columbia University Medical Center, City University of New York, and Ulm University Medical Center discuss their recent finding that FDA-approved HDAC inhibitors may have a profound effect on energy metabolism in solid cancer cells, including glioblastoma (GBM).

Given the effect of HDAC inhibitors on metabolism, we hypothesized that imiperidone, which inhibits cellular respiration, may synergize with these compounds to significantly enhance GBM cell killing. Indeed, we found that imiperidone reversed the activation of cellular respiration induced by HDAC inhibitors and, in turn, facilitated treatment. The compound induced intrinsic apoptosis in a manner that was dependent in part on the anti-apoptotic Bcl-2 family member.”

The oxidation of NADH2 and FADH2 is essential because NAD and FAD are the two essential components of the TCA cycle that are essential for the triggering of biosynthesis in cancer cells. The TCA cycle itself is fueled mostly by carbon from glucose, glutamine, fatty acids and lactate.

Targeting mitochondrial energy metabolism appears to be possible through several pharmacological compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, TCA cycle enzymes and mitochondrial matrix chaperones. While these compounds have shown anti-cancer effects in vivoRecent research indicates which patients are most likely to benefit from such therapies.

In short, targeting the metabolism of cancer cells is important, and future research needs to identify groups of patients who specifically benefit from these therapies. Furthermore, while most studies of metabolism still rely mostly on cancer cells, it is critical to expand These observations extend to the microenvironment of tumors, particularly in relation to the immune system.”