Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action

Abstract

Vicious cycles of mutations and reactive oxygen species (ROS) generation contribute to cancer progression. The use of antioxidants to inhibit ROS generation promotes cytostasis by affecting the mutation cycle and ROS-dependent survival signaling. However, cancer cells select mutations to elevate ROS albeit maintaining mitochondrial hyperpolarization (Δψm), even under hypoxia. From this perspective, the use of drugs that disrupt both ROS generation and Δψm is a viable anticancer strategy. Hence, we studied the effects of mitochondrially targeted carboxy proxyl nitroxide (Mito-CP) and a control ten carbon TPP moiety (Dec-TPP+) in the human Burkitt lymphoma cell line (Daudi) and normal peripheral blood mononuclear cells under hypoxia and normoxia. We found preferential localization, Δψm and adenosine triphosphate loss, and significant cytotoxicity by Mito-CP in Daudi cells alone. Interestingly, ROS levels were decreased and maintained in hypoxic and normoxic cancer cells, respectively, by Mito-CP but not Dec-TPP+, therefore preventing any adaptive signaling. Moreover, dual effects on mitochondrial bioenergetics and ROS by Mito-CP curtailed the cancer survival via Akt inhibition, AMPK-HIF-1α activation and promoted apoptosis via increased BCL2-associated X protein and poly (ADP-ribose) polymerase expression. This dual mode of action by Mito-CP provides a better explanation of the application of antioxidants with specific relevance to cancerous transformation and adaptations in the Daudi cell line.

Oncogenic pathways and the electron transport chain: a dangeROS liaison

“…In line with this scenario, scavenging mitochondrial O 2 •– through MitoTEMPO blunted the activation of AKT, reverted the Warburg effect and induced death in melanoma cells. 165 Moreover, Variar et al 166 observed that the mitochondria-targeted antioxidant Mito-CP enhances apoptotic cell death in a Burkitt’s lymphoma cell line by decreasing AKT activation and HIF-1α stabilisation under hypoxia, suggesting the possibility to block hypoxic adaptation in cancer cells by decreasing ROS generated by the ETC.…”