Metabolic Targets in the Crosshairs

“Mitochondria are emerging as idealized targets for anti-cancer drugs. One reason for this is that although these organelles are inherent to all cells, drugs are being developed that selectively target the mitochondria of malignant cells without adversely affecting those of normal cells. Such anticancer drugs destabilize cancer cell mitochondria and these compounds are referred to as mitocans, classified into several groups according to their mode of action and the location or nature of their specific drug targets. Many mitocans selectively interfere with the bioenergetic functions of cancer cell mitochondria, causing major disruptions often associated with ensuing overloads in ROS production leading to the induction of the intrinsic apoptotic pathway. This in-depth review describes the bases for the bioenergetic differences found between normal and cancer cell mitochondria, focusing on those essential changes occurring during malignancy that clinically may provide the most effective targets for mitocan development. A common theme emerging is that mitochondrially mediated ROS activation as a trigger for apoptosis offers a powerful basis for cancer therapy. Continued research in this area is likely to identify increasing numbers of novel agents that should prove highly effective against a variety of cancers with preferential toxicity towards malignant tissue, circumventing tumor resistance to the other more established therapeutic anti-cancer approaches”. Follow the links:

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

Choosing between glycolysis and oxidative phosphorylation: A tumor’s dilemma?

Targeting Cell Metabolism In Chronic Lymphocytic Leukaemia (CLL); A Viable Therapeutic Approach?

Stalling the Engine of Resistance: Targeting Cancer Metabolism to Overcome Therapeutic Resistance

Is Cancer a Metabolic Disease?

Cancer as a Metabolic Disease

Targeting mitochondria for cancer therapy

Mitochondrial permeability transition pore as a selective target for anti-cancer therapy

Mitochondrial uncoupling and the reprograming of intermediary metabolism in leukemia cells

Mitocans as Novel Agents for Anticancer Therapy: An Overview

Apoptosis: from biology to therapeutic targeting

 

Metabolic targets in the crosshairs

Metabolic targets in the cross hairs

 

 

 

 

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DCA – turning on OxPhos

“Inhibition of mitochondrial pyruvate dehydrogenase kinase (PDK) by dichloroacetate may be exploited to reverse the abnormal metabolism of cancer cells from glycolysis to glucose oxidation. As PDK negatively regulates pyruvate dehydrogenase, dichloroacetate indirectly stimulates the pyruvate to acetyl-CoA conversion. Dichloroacetate has been shown to downregulate the aberrantly high mitochondrial membrane potential of cancer cells, increase mitochondrial ROS generation and activate K+ channels in malignant, but not in normal cells143. Dichloroacetate also upregulated the expression of the K+ channel Kv1.5, which is often underexpressed by tumour cells, through the transcription factor nuclear factor of activated T cells (NFAT1). Dichloroacetatenormalized mitochondrial functions were accompanied by reduced proliferation, increased apoptosis and suppressed tumour growth without apparent toxicity, suggesting that the mitochondria–NFAT–Kv axis and PDK represent promising anticancer drug targets”.

Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3

The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

Targeting mitochondria for cancer therapy

738px-Dichloroacetic-acid-2D-skeletal

Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3

Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC

Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage