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Jackson AL, Sun W, Kilgore J, et al. Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. Oncotarget. 2017;8(59):100113-100127doi: 10.18632/oncotarget.22012.
Jackson, A. L., Sun, W., Kilgore, J., Guo, H., Fang, Z., Yin, Y., Jones, H. M., Gilliam, T. P., Zhou, C., & Bae-Jump, V. L. (2017). Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. Oncotarget, 8(59), 100113-100127. https://doi.org/10.18632/oncotarget.22012
Jackson, Amanda L, et al. "Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer." Oncotarget vol. 8,59 (2017): 100113-100127. doi: https://doi.org/10.18632/oncotarget.22012
Jackson AL, Sun W, Kilgore J, Guo H, Fang Z, Yin Y, Jones HM, Gilliam TP, Zhou C, Bae-Jump VL. Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. Oncotarget. 2017 Oct 24;8(59):100113-100127. doi: 10.18632/oncotarget.22012. eCollection 2017 Nov 21. PMID: 29245964; PMCID: PMC5725006.
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Oncotarget. 2017 Oct 24;8(59):100113-100127. doi: 10.18632/oncotarget.22012. eCollection 2017 Nov 21.

Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer.

Oncotarget

Amanda L Jackson, Wenchuan Sun, Joshua Kilgore, Hui Guo, Ziwei Fang, Yajie Yin, Hannah M Jones, Timothy P Gilliam, Chunxiao Zhou, Victoria L Bae-Jump

Affiliations

  1. Division of Gynecologic Oncology, University of Cincinnati, Cincinnati, OH, USA.
  2. Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  3. Houston Methodist Gynecologic Oncology Associates, Houston, TX, USA.
  4. Department of Gynecologic Oncology, Shandong Cancer Hospital & Institute, Jinan, P.R. China.
  5. Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, P.R. China.
  6. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

PMID: 29245964 PMCID: PMC5725006 DOI: 10.18632/oncotarget.22012

Abstract

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.

Keywords: AMPK/mTOR pathway; apoptosis; cell proliferation; ovarian cancer; phenformin

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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