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

Abstract

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 anti-cancer 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, focussing 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.

Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

“…Recently, it is reported that Akt in human cancer induced the glycolytic phenotype in cancer cells by phosphorylating hexokinase II to increase its association with voltage-dependent anion channel on the mitochondrial outer membrane (50). The actions of Akt render the cancer cell dependent on the availability of glucose for survival (50). Our study suggests palmitic acid is transferred from adipocytes and activates Akt in melanoma cells.…”

“…Akt signaling has been reported to regulate melanoma cell survival, migration, and metastasis and contribute to melanoma chemoresistance to therapy (29,49). Recently, it is reported that Akt in human cancer induced the glycolytic phenotype in cancer cells by phosphorylating hexokinase II to increase its association with voltage-dependent anion channel on the mitochondrial outer membrane (50). The actions of Akt render the cancer cell dependent on the availability of glucose for survival (50).…”

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

“…OGDH is a well-characterized auto-antigen in primary biliary cirrhosis. The activity of the enzyme is much lower in Alzheimer's disease, and there are reports of the enzyme's susceptibility to modification by oxidative stress [29] . Inhibition of OGDH activity alleviates glutamate-induced calcium deregulation, mitochondrial depolarization, and neuronal death [30] .…”

Metabolic reprogramming of the tumor

“…Many pharmacological agents able to specifically target these organelles in malignant cells without affecting their normal counterparts are being developed (Ralph et al, 2010). The tumor suppression of mitochondrial respiration would decrease endogenous ROS generation, as inhibition of H þ -ATP synthase has been shown to delay ROSdependent cell death (Santamaria et al, 2006).…”