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Circumvention of atypical multidrug resistance with tumor necrosis factor
G Cimoli1, M Valenti, S Parodi
1Department of Chemical Carcinogenesis, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Abstract:
Some "multidrug-resistant" (MDR) cell lines are not associated with a defect in drug accumulation or with the overexpression of P-glycoprotein. These cell lines are defined as "atypical MDR" (at-MDR) and they often express altered or mutated topoisomerase II. We investigated the ability of tumor necrosis factor to reverse at-MDR (in the human ovarian cancer cell line A2780 DX3) on the basis of its efficacy in potentiating in vitro topoisomerase II-targeted drugs, and because there is convincing evidence that the synergy is due to an increased number of topoisomerase-associated strand-breaks as well as to an increased level of extractable topoisomerase.
Insights
Tumor necrosis factor can reverse atypical multidrug resistance (at-MDR) in ovarian cancer cells. This occurs by enhancing topoisomerase II activity and increasing DNA strand breaks, making cancer cells more sensitive to chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Some multidrug-resistant (MDR) cancer cell lines exhibit atypical resistance (at-MDR).
- These cell lines lack typical resistance mechanisms like reduced drug accumulation or P-glycoprotein overexpression.
- Atypical MDR is often linked to alterations in topoisomerase II, a key enzyme in DNA replication and repair.
Purpose of the Study:
- To investigate the potential of tumor necrosis factor (TNF) in reversing atypical multidrug resistance (at-MDR).
- To evaluate TNF's efficacy in sensitizing at-MDR ovarian cancer cells (A2780 DX3) to topoisomerase II-targeted drugs.
- To elucidate the mechanisms underlying TNF-induced reversal of at-MDR.
Main Methods:
- Utilized the human ovarian cancer cell line A2780 DX3, known for its atypical multidrug resistance.
- Administered tumor necrosis factor (TNF) in combination with topoisomerase II-targeted chemotherapeutic agents.
- Assessed changes in topoisomerase II activity, DNA strand breaks, and drug sensitivity in treated cells.
Main Results:
- Tumor necrosis factor demonstrated the ability to reverse atypical multidrug resistance in the A2780 DX3 cell line.
- TNF treatment led to a significant potentiation of topoisomerase II-targeted drugs.
- The observed synergy was associated with an increased number of topoisomerase-associated DNA strand breaks and elevated levels of extractable topoisomerase.
Conclusions:
- Tumor necrosis factor is a viable agent for overcoming atypical multidrug resistance in ovarian cancer.
- TNF enhances the efficacy of topoisomerase II-targeted therapies by increasing DNA damage.
- Targeting topoisomerase II in conjunction with TNF may represent a promising strategy for treating resistant ovarian cancers.