Antidiabetic Drugs Influence Molecular Mechanisms in Prostate Cancer

Cancer Biol Ther. 2018;19(12):1153-1161. doi: 10.1080/15384047.2018.1491490. Epub 2018 Aug 1.

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.

Keywords: Prostate cancer; aggressiveness; insulin; metformin; molecular pathways; mortality.

MeSH terms

  • Aged
  • Biomarkers
  • Biopsy
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Prostatic Neoplasms / complications*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / metabolism
  • Recurrence

Substances

  • AR protein, human
  • Biomarkers
  • Hypoglycemic Agents
  • Receptors, Androgen