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Updated: Jan 30, 2026
A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation
Published on: July 13, 2018
Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia
Sébastien Marx1, Mégane Van Gysel1, Aurélie Breuer1
1Department of Chemistry, NAmur MEdicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium.
Abstract:
Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and chemotherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression. Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxia compared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells in normoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiate their activity in low oxygen environment could be a strategy to counteract this resistance. To identify new compounds active in hypoxia, we screened one hundred molecules with different chemical structures from an internal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently of their mechanism of action has been assayed. After a first step of selection, based on biological/pharmacological properties and chemical structure analysis, we identified three potential hits. Two hits are closely related amides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normal cells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death, the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol and etoposide in two models of cancer cell lines. This new compound could lead to the development of an original series of chemosensitizers active under hypoxia.
Insights
Hypoxia increases cancer aggressiveness and chemotherapy resistance. Researchers identified novel compounds, including an indole thiosemicarbazone, that enhance chemotherapy effectiveness in low-oxygen tumor environments.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Hypoxia significantly impacts cancer aggressiveness and resistance to chemotherapy.
- Conventional cancer therapies are less effective under hypoxic conditions, necessitating new strategies.
- Tumor microenvironments exhibit altered pH, matrix remodeling, and neo-angiogenesis alongside hypoxia.
Purpose of the Study:
- To identify novel compounds that enhance the efficacy of existing chemotherapies under hypoxic conditions.
- To counteract chemoresistance developed by cancer cells in low-oxygen environments.
- To discover new chemosensitizers with potential for original therapeutic development.
Main Methods:
- Screened 100 diverse molecules from an internal chemolibrary for their ability to potentiate taxol and etoposide activity.
- Selected potential hits based on biological/pharmacological properties and chemical structure analysis.
- Assayed chemosensitizing activity under hypoxia and analyzed cell death to confirm apoptosis potentiation.
Main Results:
- Identified three potential hits: two amides/ureas and one thiosemicarbazone.
- Selected compounds showed no intrinsic activity in cancer or normal cells but demonstrated chemosensitizing effects under hypoxia.
- The indole thiosemicarbazone significantly potentiated taxol- and etoposide-induced apoptosis in two cancer cell line models.
Conclusions:
- The indole thiosemicarbazone is a promising chemosensitizer effective in hypoxic cancer cells.
- This compound could form the basis for a new class of hypoxia-activated anticancer agents.
- Targeting hypoxia-induced chemoresistance represents a viable strategy for improving cancer treatment outcomes.
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