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A decreasing function describes a relationship where the output consistently declines as the input increases. This means that for any two input values, if one is greater than the other, the corresponding output is smaller. Mathematically, a function f is decreasing on an interval I if for every x1 < x2​ in I, f (x1) > f (x2). This type of behavior is visually identified on a graph that slopes downward from left to right.The nature of a function can be analyzed by calculating...
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Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption.

Sven de Mey1, Heng Jiang1, Cyril Corbet2

  • 1Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Frontiers in Pharmacology
|October 20, 2018
PubMed
Summary
This summary is machine-generated.

Metformin and phenformin, biguanide drugs, overcome cancer cell radioresistance under hypoxia by inhibiting mitochondrial respiration. This suggests their potential as radiosensitizers when combined with radiation therapy.

Keywords:
colorectal cancerhypoxic radiosensitivitymetforminmitochondrial complex Ioxygen consumption ratephenformin

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Area of Science:

  • Biochemistry
  • Oncology
  • Pharmacology

Background:

  • Biguanide drugs metformin and phenformin show antitumor properties.
  • Their role in modulating radioresistance under hypoxia is largely unexplored.

Purpose of the Study:

  • To investigate if metformin and phenformin can overcome hypoxic radioresistance.
  • To determine if this effect is mediated by inhibiting oxygen consumption via mitochondrial complex I blockade.

Main Methods:

  • Colorectal cancer cells were treated with metformin or phenformin.
  • Cell viability, apoptosis, ROS, and AMPK phosphorylation were assessed.
  • Mitochondrial activity and oxygen consumption rate (OCR) were measured.
  • Radiosensitivity was evaluated under aerobic and hypoxic conditions.
  • In vivo studies in a colorectal tumor model were conducted.

Main Results:

  • Metformin and phenformin inhibited mitochondrial complex I and reduced OCR.
  • Both drugs counteracted hypoxic radioresistance, enhancing radiosensitivity.
  • No effect on intrinsic radioresistance was observed, despite increased AMPK phosphorylation and ROS.
  • In vivo, combined treatment with radiation significantly delayed tumor growth and improved radioresponse.

Conclusions:

  • Metformin and phenformin overcome hypoxic radioresistance by inhibiting mitochondrial respiration.
  • These findings support the exploration of metformin and phenformin as hypoxic radiosensitizers in cancer therapy.