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Mitochondrial uncoupler MB1-47 is efficacious in treating hepatic metastasis of pancreatic cancer in murine tumor transplantation models

Abstract

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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Fig. 1: The schematic of the mitochondrial uncoupling mechanism and the synthetic route of MB1-47.
Fig. 2: MB1-47 uncouples mitochondria in pancreatic cancer cells.
Fig. 3: Effect of MB1-47 on pancreatic cancer cell metabolism.
Fig. 4: Effect of MB1-47 on cell cycle progression, clonogenicity, and cell proliferation of pancreatic cancer cells.
Fig. 5: MB1-47 inhibits the growth of intrahepatically transplanted Panc02 cancer cells.
Fig. 6: MB1-47 inhibits liver metastasis of the intrasplenically injected Panc02 cells.
Fig. 7: MB1-47 increases phosphorylation of AMPK and ACC and downregulates mTOR activities in the pancreatic cancer cells.

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Acknowledgements

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).

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Conception and design: SJ and AA. Development of methodology: AA, SJ, BC, and DA. Acquisition of data: BC synthesized the compound, AA conducted most of the biological experiments, AA and HT conducted OCR Seahorse experiment, AA, JG, and XS conducted the LC-MS experiment. Analysis and interpretation of data (e.g., statistical analysis, LC-MS): AA, XS, and SJ. Writing, review, and/or revision of the paper: AA and SJ. Study supervision: SJ.

Corresponding author

Correspondence to Shengkan Jin.

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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

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