Antidiabetic drugs influence molecular mechanisms in prostate cancer

Abstract

Background: We investigated the role of diabetes mellitus (DM) and the molecular mechanisms of antidiabetic drugs in prostate cancer (PCa). Patients and Methods: 167 patients with both DM and PCa underwent radical prostatectomy (RPE). We divided our patient collective into "metformin" users, "insulin" users, "other antidiabetic drug" users and those with "no antidiabetic drug/diet only" (control group) and analyzed differences in PCa aggressiveness and laboratory parameters among treatment groups. In addition, we generated a tissue-micro-array (TMA) from RPE specimens for the analysis of candidate target pathways of antidiabetic drugs by immunohistochemistry (IHC). Results: Gleason score of both biopsy and RPE, biopsy undergrading, tumor stage as well as positive resection margins did not significantly change among groups. Preoperative body mass-index, PSA, fPSA and prostate volume/weight did not change among the treatment groups. As well, CRP, GOT, GPT, yGT, LDH, amylase, hemoglobin, TSH, FT3 and FT4 did not differ. Metformin or insulin use was not associated with changes in biochemical tumor recurrence or PCa specific mortality rates. However, tissue TMA analyses by IHC showed decreased mTOR activation, as indicated by phospho-mTOR in cancer tissue of patients with metformin and also with insulin use compared to the control group. In addition, we were able to show that the androgen receptor and the epithelial-cell contact marker E-cadherin decreased upon metformin use compared to the control group. Conclusion: We did not find a connection between antidiabetic drugs and PCa aggressiveness or progression. However, tumor biology seems to be different among patients with and without antidiabetic drugs.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…MF is also used to treat non-alcoholic fatty liver disease [ 3 ], coronary artery disease [ 4 , 5 ], acute kidney injury and chronic kidney disease [ 6 ], in patients with T2DM, metabolic syndrome (MetS) and obesity, and in patients without apparent symptoms of metabolic disorders [ 7 ]. There are numerous clinical and experimental studies indicating the effectiveness of MF as an anticancer drug, used to prevent the growth and metastasis in breast cancer [ 8 , 9 ], endometrial cancer [ 10 , 11 , 12 ], colorectal cancer [ 9 , 13 ], prostate cancer [ 14 ] and in a number of the other tumors [ 15 , 16 ].…”

Association of type 2 diabetes mellitus and antidiabetic medication with risk of prostate cancer: a population-based case-control study

“…The results demonstrate a persistently decreased risk of PCa for all anti-diabetic medications and durations. One possible explanation for this observation is that metformin and insulin are thought to reduce the activity of mTOR, which blocks progression of the cell cycle and cancer growth [26,27]. For example, Pircher et al conducted a study exploring antidiabetic drugs that influence molecular mechanisms in prostate cancer and showed that insulin use significantly decreased active mTOR in cancer tissue [26].…”

“…One possible explanation for this observation is that metformin and insulin are thought to reduce the activity of mTOR, which blocks progression of the cell cycle and cancer growth [26,27]. For example, Pircher et al conducted a study exploring antidiabetic drugs that influence molecular mechanisms in prostate cancer and showed that insulin use significantly decreased active mTOR in cancer tissue [26]. In addition, they found an AMPK and AKT independent regulation of the mTOR pathway, as there were no differences in pAKT levels among treatment groups (insulin and metformin groups) [26].…”

“…For example, Pircher et al conducted a study exploring antidiabetic drugs that influence molecular mechanisms in prostate cancer and showed that insulin use significantly decreased active mTOR in cancer tissue [26]. In addition, they found an AMPK and AKT independent regulation of the mTOR pathway, as there were no differences in pAKT levels among treatment groups (insulin and metformin groups) [26]. Hence, medication that can attenuate mTOR activity with subsequent blockade of cell cycle progression, can potentially also block the progression of the prostate cell cycle and cancer growth [28].…”

Association of type 2 diabetes mellitus and antidiabetic medication with risk of prostate cancer: a population-based case-control study.

“…The results demonstrate a persistently decreased risk of PCa for all anti-diabetic medications and durations. Metformin and insulin reduce the activity of mTOR, which blocks progression of the cell cycle and cancer growth [26,27], giving a possible biological mechanism for the reduction in risk. However, other studies have shown no protective effect of metformin and insulin on PCa risk [14,[28][29][30].…”