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

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.

Mitochondrial targets of metformin—Are they physiologically relevant?

“…57 Inherent risk connected with complex I inhibition is development of lactic acidosis. 3 It was published that more lipophilic metformin analogues, phenformin and buformin, have more potent antitumor effect, 58,59 but they are also more likely to trigger lactic acidosis. 3 Even metformin, which is considered relatively safe in this regard, may present higher risk of lactic acidosis in patients with associated condition, such as renal impairment, which increases metformin levels in plasma.…”

Mitochondria in cancer metabolism, an organelle whose time has come?

“…Metformin is currently being tested in several clinical trials. A precursor molecule Phenformin, was taken off the market for diabetes due to its increased risk of lactic acidosis but has efficacy in against multiple cancer cell lines and preclinical models [40–44]. Phenformin is not reliant on transporters for cell entry and has increased potency for the mitochondrial membrane compared to metformin [45].…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Phenformin also exerted antiproliferative effects in seven primary cell cultures of human ovarian cancer. In this study, phenformin also inhibited tumour growth in an orthotopic mouse model of serous ovarian cancer …”

“…In this study, phenformin also inhibited tumour growth in an orthotopic mouse model of serous ovarian cancer. 40 Clinically, Type 2 diabetes mellitus has been linked with increased risk of cancers such as those of colon/rectum, breast, bladder and pancreas, 41,42 and treatment of diabetes with metformin is reported to reduce the risk of cancers. 43,44 Diabetes is also a prognostic factor that influences clinical outcomes in cancer.…”