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Tully E, Bharti S, Woo J, et al. Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells. Cancer Biol Ther. 2021;22(10):579-586doi: 10.1080/15384047.2021.1982599.
Tully, E., Bharti, S., Woo, J., Bhujwalla, Z., & Gabrielson, E. (2021). Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells. Cancer biology & therapy, 22(10), 579-586. https://doi.org/10.1080/15384047.2021.1982599
Tully, Ellen, et al. "Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells." Cancer biology & therapy vol. 22,10 (2021): 579-586. doi: https://doi.org/10.1080/15384047.2021.1982599
Tully E, Bharti S, Woo J, Bhujwalla Z, Gabrielson E. Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells. Cancer Biol Ther. 2021 Dec 02;22(10):579-586. doi: 10.1080/15384047.2021.1982599. Epub 2021 Oct 31. PMID: 34720054; PMCID: PMC8726685.
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Cancer Biol Ther. 2021 Dec 02;22(10):579-586. doi: 10.1080/15384047.2021.1982599. Epub 2021 Oct 31.

Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells.

Cancer biology & therapy

Ellen Tully, Santosh Bharti, Juhyung Woo, Zaver Bhujwalla, Edward Gabrielson

Affiliations

  1. The Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  2. The Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  3. The Department of Oncology and the Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

PMID: 34720054 PMCID: PMC8726685 DOI: 10.1080/15384047.2021.1982599

Abstract

Biguanide drugs (metformin and phenformin) have drawn interest for potential cancer treatments, and laboratory studies show that some cancer cells are selectively sensitive to growth-inhibitory effects of biguanides. Examining metabolic pathways affected by biguanide treatments in cancer cells that are highly sensitive to biguanides, we found that biguanide treatment depletes cellular levels of both aspartate and NAD+. Experiments to replenish these metabolites or block steps of the aspartate-malate shuttle suggest that depletion of both metabolites, rather than either aspartate of NAD+ individually, is critical for growth-inhibitory effects of biguanide exposure. Even in sensitive cancer cells, though, biguanide treatment alone over a broad range of doses only inhibits cell replication without significantly affecting cell viability. Noting that clinical observations of biguanide efficacy have used combinations of agents that typically include cisplatin, we found that biguanide treatment at a cytostatic level substantially decreases survival of lung cancer and breast cancer cells when co-treated with cisplatin at doses that alone are also non-cytotoxic. This striking enhancement of cisplatin toxicity by biguanides depends on reductions of levels of NAD+ and aspartate, since addition of either of these metabolites prevented this potentiation of cisplatin cytotoxicity. Thus, biguanide drugs can have cytotoxic effects when used in combination with other cancer drugs, such as cisplatin, and depleting cellular levels of NAD+ and aspartate is critical for enhancing the cytotoxicity of cisplatin by biguanide drugs in sensitive cancer cells.

Keywords: Biguanides; aspartate; cisplatin; metformin; nad; phenformin

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