Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED)

Alghandour, Reham; Ebrahim, Mohamed A.; Elshal, Ahmed M.; Ghobrial, Fady K.; Elzaafarany, Maha; Elbaiomy, Mohamed

doi:10.1016/j.urolonc.2021.05.020

Cited by 27 publications

(21 citation statements)

References 27 publications

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Section: Discussionsupporting

confidence: 92%

“…Metformin has been associated with cancer, but this interplay is poorly understood in relation to HRCs (prostate, colorectal and male breast cancer) and among men of different racial backgrounds. 3,12,34,35 Our findings are in agreement with a previous study retrospective cohort study that significant associations between metformin and incident prostate and colorectal cancers. 1 However, a meta-analysis of 18 cohort studies did not show an association between metformin and prostate cancer, 12 prostate cancer mortality, 2 and another study did not show improvement in survival in women with breast cancer.…”

Section: Metformin Use and Prostate Colorectal And Breast Cancers And...supporting

confidence: 93%

“…The effect of metformin on the reduction of overall cancer risk has been previously observed, but it merits a further observation with prostate, colorectal and male breast cancers, stage and grade at diagnosis, and cancer site-specific mortality. [1][2][3] Because endogenous testosterone has been previously associated with prostate, colorectal and male breast cancer, they will be referred as hormone-associated cancers, HRCs, when they are combined. [4][5][6][7][8][9][10][11] Colorectal cancer is investigated as a hormone-associated cancer and not as a hormonedependent or hormone-caused cancer; therefore, this potential hormone-cancer relationship has potential translational applications for preventive diagnosis, risk stratification and treatment.…”

mentioning

confidence: 99%

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Metformin and testosterone replacement therapy inversely associated with hormone‐associated cancers (prostate, colorectal and male breast cancers) among older White and Black men

López

Malagaris

Polychronopoulou

et al. 2022

Clinical Endocrinology

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Background The independent and joint association of metformin and testosterone replacement therapy (TTh) with the incidence of prostate, colorectal, and male breast cancers remain poorly understood, including the investigation of the risk of these cancers combined (HRCs, hormone‐associated cancers) among men of different racial and ethnic background. Methods In 143,035 men (≥ 65 yrs old) of SEER‐Medicare 2007–2015, we identified White (N = 110,430), Black (N = 13,520) and Other Race (N = 19,085) men diagnosed with incident HRC. Pre‐diagnostic prescription of metformin and TTh was ascertained for this analysis. Weighted multivariable‐adjusted conditional logistic and Cox proportional hazards models were conducted. Results We found independent and joint associations of metformin and TTh with incident prostate (odds ratio [OR]joint = 0.44, 95% confidence interval [CI]: 0.36–0.54) and colorectal cancers (ORjoint = 0.47, 95% CI: 0.34–0.64), but not with male breast cancer. There were also inversed joint associations of metformin and TTh with HRCs (ORjoint = 0.45, 95% CI: 0.38–0.54). Similar reduced associations with HRCs were identified among White, Black, and Other Race men. Conclusion Pre‐diagnostic use of metformin and TTh were, independently and jointly, inversely associated with incident prostate and colorectal cancers. The risk of HRCs was also reduced among White, Black and Other Race men. Greatest reduced associations of prostate and colorectal cancers and HRCs were mainly observed in combination of metformin and TTh. Larger studies are needed to confirm the independent and joint association of metformin plus TTh with these cancers in understudied and underserved populations.

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Section: Discussionsupporting

confidence: 92%

Section: Metformin Use and Prostate Colorectal And Breast Cancers And...supporting

confidence: 93%

mentioning

confidence: 99%

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Metformin and testosterone replacement therapy inversely associated with hormone‐associated cancers (prostate, colorectal and male breast cancers) among older White and Black men

López

Malagaris

Polychronopoulou

et al. 2022

Clinical Endocrinology

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“…We screened 8419 records and identified 22 eligible trials (5943 participants) in the final meta-analysis (Fig. 1 ) [ 30 – 52 ]. All the studies were RCTs published between 2015 and 2022.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials

Wen

Chen

et al. 2022

BMC Med

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Background To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). Methods Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries (ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. Results Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82–1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86–1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74–1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03–2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. Conclusion Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. Systematic review registration PROSPERO registration number CRD42022324672.

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“…Metformin, which is widely used as anti-diabetic drug, has demonstrated important anti-cancer effects both in vitro and in vivo in many studies [16][17][18]. Metformin combination with other treatment strategies has also been widely reported [19].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway

Tang¹,

Chen²,

Liu³

et al. 2022

J. Cancer

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.

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Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED)

Cited by 27 publications

References 27 publications

Metformin and testosterone replacement therapy inversely associated with hormone‐associated cancers (prostate, colorectal and male breast cancers) among older White and Black men

Metformin and testosterone replacement therapy inversely associated with hormone‐associated cancers (prostate, colorectal and male breast cancers) among older White and Black men

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials

Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway

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