Canonical and new generation anticancer drugs also target energy metabolism

Abstract

Significant efforts have been made for the development of new anticancer drugs (protein kinase or proteasome inhibitors, monoclonal humanized antibodies) with presumably low or negligible side effects and high specificity. However, an in-depth analysis of the side effects of several currently used canonical (platin-based drugs, taxanes, anthracyclines, etoposides, antimetabolites) and new generation anticancer drugs as the first line of clinical treatment reveals significant perturbation of glycolysis and oxidative phosphorylation. Canonical and new generation drug side effects include decreased (1) intracellular ATP levels, (2) glycolytic/mitochondrial enzyme/transporter activities and/or (3) mitochondrial electrical membrane potentials. Furthermore, the anti-proliferative effects of these drugs are markedly attenuated in tumor rho (0) cells, in which functional mitochondria are absent; in addition, several anticancer drugs directly interact with isolated mitochondria affecting their functions. Therefore, several anticancer drugs also target the energy metabolism, and hence, the documented inhibitory effect of anticancer drugs on cancer growth should also be linked to the blocking of ATP supply pathways. These often overlooked effects of canonical and new generation anticancer drugs emphasize the role of energy metabolism in maintaining cancer cells viable and its targeting as a complementary and successful strategy for cancer treatment.

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism

“…Emerging research indicates development of new generation anticancer drugs targeting energy metabolism [33,34]. We reported that mitochondria targeted cationic drugs selectively inhibit ATP-linked mitochondrial respiration in tumor cells and potently activate AMP-activated protein kinase (AMPK) in human PDAC [23].…”

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

“…Thus, a better understanding of cancer cell metabolism may pave the way for designing targeted anticancer drugs that are more effective and less toxic (to normal cells). Recent developments in cancer drug discovery focus on inhibitors of metabolic pathways exploited by cancer cells [8], [9], [10]. As opposed to cytotoxic therapies (chemotherapy and radiation) that kill cancer cells and result in tumor shrinkage quickly after therapy, targeted therapies do not immediately kill cancer cells [11].…”

Overview of Research and Development for Anticancer Drugs

“…Targeting both processes may thus be selectively cytotoxic for cancer cells [37]. Multiple glycolytic targets related to this complex biochemical process has been studied and under developing including lactate dehydrogenase which catalyzes the reduction of pyruvate by reduced nicotinamide adenine dinucleotide to form lactate [38] [39], poly (ADPribose) polymerases which utilize oxidized nicontinamide adenine dinucleotide as a substrate to catalyze the attachment of ADP-ribose polymers to target proteins [37] [40], energy metabolism links to ATP supply pathways [41] [42], a nucleotide pool sanitizing enzyme protein which sanitizes oxidized dNTP pools to prevent incorporation of damaged bases produced by increased ROS in cancer cells [19] [43] [44]. Based on the preclinical success of both approaches, some metabolic inhibitors of these targets are now entering clinical trials (http://www.clinicaltrials.gov/) [37].…”