Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer characterized by rapid progression, metastatic recurrence, and highly resistant to treatment. PDA cells exhibit aerobic glycolysis, or the Warburg effect, which reduces the flux of pyruvate into mitochondria. As a result, more glycolytic metabolites are shunted to pathways for the production of building blocks (e.g., ribose) and reducing agents (e.g., NADPH) for biosynthesis that are necessary for cell proliferation. In addition, PDA cells are highly addicted to glutamine for both maintaining biosynthetic pathways and achieving redox balance. Mitochondrial uncoupling facilitates proton influx across the mitochondrial inner membrane without generating ATP, leading to a futile cycle that consumes glucose metabolites and glutamine. We synthesized a new mitochondrial uncoupler MB1-47 and tested its effect on cancer cell metabolism and the anticancer activity in pancreatic cancer cell models and murine tumor transplantation models. MB1-47 uncouples mitochondria in the pancreatic cancer cells, resulting in: (1) the acceleration of pyruvate oxidation and TCA turnover; (2) increases in AMP/ATP and ADP/AMP ratios; and (3) a decrease in the synthesis rate of nucleotides and sugar nucleotides. Moreover, MB1-47 arrests cell cycle at G0–G1 phase, reduces clonogenicity, and inhibits cell growth of murine and human pancreatic cancer cells. In vivo studies showed that MB1-47 inhibits tumor growth in murine tumor transplantation models, and inhibits the hepatic metastasis when tumor cells were transplanted intrasplenically. Our results provide proof of concept for a potentially new strategy of treating PDA, and a novel prototype experimental drug for future studies and development.
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The authors want to thank Frank Leu for reviewing and editing the paper. The project was partially funded by Rutgers Busch Biomedical Award (2014), HCED Iraq Scholarship program, New Jersey Cancer Commission Research (NJCCR) Fellowship, and Mito BioPharma, LLC. AA is supported by HCED Iraq Scholarship program. HT was supported in part by NJCCR. AA, HT, JG, and SJ are partially supported by NIH (1R21CA216604 and 1R21 AA027050).
Conflict of interest
SJ is a founder of Mito BioPharma, which has a license right from Rutgers University for developing safe mitochondrial uncouplers for treating cancer and metabolic diseases. BC, HT, and DA are co-inventors of the patents covering the rights of MB1-47 and its derivatives. The rest of the authors declare no competing interests.
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Alasadi, A., Cao, B., Guo, J. et al. Mitochondrial uncoupler MB1-47 is efficacious in treating hepatic metastasis of pancreatic cancer in murine tumor transplantation models. Oncogene 40, 2285–2295 (2021). https://doi.org/10.1038/s41388-021-01688-7