Mitochondrial Alteration: A Major Player in Carcinogenesis

Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of β-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted β-lapachone is more efficient in inducing apoptosis compared to unconjugated β-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated β-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting β-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy.

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Metabolic Imbalance Associated Mitophagy in Tumor Cells: Genesis and Implications

Chaurasia

Misra

Bhatt

et al. 2015

J. Can. Res. Updates

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Emerging knowledge supports the notion that metabolic reprogramming facilitates the progression of many cancers and in some it could be initiated by mutations in genes related to mitochondrial function. While dysfunctional mitochondria plays a pivotal role in driving metabolic reprogramming, mitophagy that recycles damaged mitochondria by selective and organized degradation appears to be vital for sustaining carcinogenesis. Although the potential of targeting mitophagy as a therapeutic strategy has still remained elusive, poor prognosis and therapeutic resistance of highly glycolytic tumors suggest that inhibitors of mitophagy could be potential adjuvant in radio- and chemotherapy of tumors. We briefly review the current status of knowledge on the interrelationship between mitophagy and metabolic reprogramming during carcinogenesis and examine mitophagy as a potential target for developing anticancer therapeutics and adjuvant.

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Mitochondrial Alteration: A Major Player in Carcinogenesis

Cited by 3 publications

References 81 publications

Analysis of mitochondrial DNA copy number variation in blood and tissue samples of metastatic breast cancer patients (A pilot study)

Analysis of mitochondrial DNA copy number variation in blood and tissue samples of metastatic breast cancer patients (A pilot study)

Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells

Metabolic Imbalance Associated Mitophagy in Tumor Cells: Genesis and Implications

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