Abstract
Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-3C, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues. Here, we investigated the cytotoxic mechanism of salt 1-3C compared to its analogue, salt 1-8C, with an extended side carbon chain. Live cell imaging demonstrated that salt 1-3C, but not 1-8C, is rapidly incorporated into mitochondria, correlating with increased cytotoxicity of salt 1-3C. The accumulation in mitochondria led to their fragmentation and loss of function, accompanied by increased autophagy/mitophagy. Salt 1-3C preferentially activated AMP-activated kinase and inhibited mammalian target of rapamycin (mTOR) signaling pathways, sensors of cellular metabolism, but did not induce apoptosis. These data indicate that salt 1-3C cytotoxicity involves mitochondrial perturbation and disintegration, and such compounds are promising candidates for targeting mitochondria as a weak spot of cancer.
Highlights
Mitochondria play a crucial role in the metabolism of eukaryotic organisms
We demonstrate that salt 1-3C is rapidly incorporated into mitochondria, disrupting mitochondrial structure and function, which is followed by metabolic stress and leading to death of cancer cells through a non-apoptotic mechanism
To elucidate the effect of salt 1-3C on mitochondrial fragmentation, we further explored the mitochondrial membrane potential (MMP)
Summary
Mitochondria play a crucial role in the metabolism of eukaryotic organisms. Their principal and most well-known function is to provide cells with energy in the form of ATP through oxidative respiration, they are important for the production and utilization of many metabolic intermediates of nucleotide synthesis and lipid metabolism, and for regulating redox balance [1]. Mitochondria are well known to exhibit altered function and activity in tumor cells and are involved in redeployment of metabolic intermediates to meet the biosynthetic requirements of proliferation and increased NADPH production to maintain cellular redox status [2,3]. Many compounds have been developed recently to selectively accumulate in mitochondria, including new experimental drugs and molecular probes that are enabling researchers to study mitochondrial processes in detail [6,7]. Rhodamine [9], an alkyltriphenylphosphonium moiety [10], or cyanine cations [11] have been linked to biologically active molecules to study mitochondrial activities in a wide range of physiological and pathological conditions
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