Toxicology and applied pharmacology · 2026
Brefeldin A induces apoptosis in cisplatin-resistant ovarian cancer cells independent of ABCC2-mediated drug efflux.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Haghi Seyedeh Mona, Tavakkoli Alireza, Iranshahi Mehrdad, Kalalinia Fatemeh, Hashemi Maryam, Najafzadeh Mohammad Javad, Mosaffa Fatemeh
Аннотация
BACKGROUND: Resistance to platinum chemotherapy remains a major obstacle in ovarian cancer treatment and is often associated with overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters such as ABCC2. Agents that retain cytotoxic efficacy in resistant cells through transporter-independent mechanisms may provide a therapeutic advantage.
METHODS & MATERIALS: Brefeldin A (BFA), a fungal metabolite with known anticancer activity, was isolated from the endophytic fungus Dactylonectria torresensis and characterized by nuclear magnetic resonance (NMR) spectroscopy. Cytotoxicity and chemosensitization were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays in cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cell line (A2780/RCIS). Cisplatin efflux transporter expression level was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), while transporter activity was assessed by flow cytometry using 5-carboxyfluorescein diacetate (5-CFDA). Cell cycle distribution and apoptosis-associated cell death (based on Sub-G1 accumulation) were examined by propidium iodide (PI) staining and flow cytometry.
RESULTS: BFA exhibited comparable cytotoxicity in sensitive and resistant cells (inhibitory concentration (IC)₅₀ 47.2 ± 2.3 and 53.6 ± 3.8 nM, respectively), indicating that ABCC2 overexpression in resistant cells did not affect cellular responsiveness. Treatment with a non-cytotoxic concentration of BFA did not alter ABCC1/ABCC2 expression or transporter activity. Instead, co-treatment with cisplatin and BFA enhanced G2/M cell cycle arrest and increased the Sub-G1 population in both cell lines, consistent with apoptosis-associated cell death. Co-treatment resulted in a modest increase in cisplatin-induced growth inhibition, suggesting apoptotic priming rather than efflux inhibition.
CONCLUSION: BFA maintains cytotoxic efficacy in cisplatin-resistant ovarian cancer cells through apoptosis-associated mechanisms that are independent of ABCC2-mediated drug efflux. These findings indicate that BFA avoids classical transporter-mediated resistance and could be a candidate for targeting drug-resistant ovarian cancer.
METHODS & MATERIALS: Brefeldin A (BFA), a fungal metabolite with known anticancer activity, was isolated from the endophytic fungus Dactylonectria torresensis and characterized by nuclear magnetic resonance (NMR) spectroscopy. Cytotoxicity and chemosensitization were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays in cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cell line (A2780/RCIS). Cisplatin efflux transporter expression level was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), while transporter activity was assessed by flow cytometry using 5-carboxyfluorescein diacetate (5-CFDA). Cell cycle distribution and apoptosis-associated cell death (based on Sub-G1 accumulation) were examined by propidium iodide (PI) staining and flow cytometry.
RESULTS: BFA exhibited comparable cytotoxicity in sensitive and resistant cells (inhibitory concentration (IC)₅₀ 47.2 ± 2.3 and 53.6 ± 3.8 nM, respectively), indicating that ABCC2 overexpression in resistant cells did not affect cellular responsiveness. Treatment with a non-cytotoxic concentration of BFA did not alter ABCC1/ABCC2 expression or transporter activity. Instead, co-treatment with cisplatin and BFA enhanced G2/M cell cycle arrest and increased the Sub-G1 population in both cell lines, consistent with apoptosis-associated cell death. Co-treatment resulted in a modest increase in cisplatin-induced growth inhibition, suggesting apoptotic priming rather than efflux inhibition.
CONCLUSION: BFA maintains cytotoxic efficacy in cisplatin-resistant ovarian cancer cells through apoptosis-associated mechanisms that are independent of ABCC2-mediated drug efflux. These findings indicate that BFA avoids classical transporter-mediated resistance and could be a candidate for targeting drug-resistant ovarian cancer.