恩杂鲁胺通过细胞凋亡克服二氢睾酮诱导的三阴性乳腺癌细胞化疗耐药,Anti-Cancer Agents in Medicinal Chemistry

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恩杂鲁胺通过细胞凋亡克服二氢睾酮诱导的三阴性乳腺癌细胞化疗耐药
Anti-Cancer Agents in Medicinal Chemistry ( IF 2.6 ) Pub Date : 2022-05-11 , DOI: 10.2174/1871520622666220509123505
Laila Alsawalha ₁ , Mamoun Ahram ₂ , Mohammad S Abdullah ₂ , Ozlem Dalmizrak ₁

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背景：由于其异质性和缺乏治疗靶点，三阴性乳腺癌的治疗具有挑战性。因此，全身化疗仍是TNBC治疗的主要手段。不幸的是，患者通常会产生化学抗性。通过其受体的雄激素信号传导是乳腺癌的重要参与者，它已被证明赋予 TNBC 细胞化学抗性。目的：本研究的目的是阐明恩杂鲁胺通过细胞凋亡途径在 TNBC 细胞对多柔比星的化学反应中的机制作用。方法：以MDA-MB-231和MDA-MB-453细胞作为TNBC的模型系统。在二氢睾酮 (DHT) 和/或恩杂鲁胺存在下用多柔比星处理细胞后研究细胞活力和细胞凋亡。进行 Caspase 3/7 活性和 TUNEL 测定以评估细胞凋亡的诱导。通过 qPCR 检测细胞凋亡调节基因的表达，以检测表达变化。结果：恩杂鲁胺降低了 MDA-MB-231 和 MDA-MB-453 细胞的活力，并降低了两种细胞系的 DHT 诱导的化学抗性。它还增加了 MDA-MB-231 细胞对多柔比星的化学敏感性。这些结果伴随着 DNA 降解和 caspase 3/7 活性的增加。此外，enzalutamide 下调 MDA-MB-231 细胞中抗凋亡基因 mcl1 和 bcl2 的表达，同时增加促凋亡基因 bid 的表达。另一方面，DHT 上调了两种细胞系中抗凋亡基因 mcl1 和 bcl2 的表达。结论：DHT 增加了 TNBC 细胞中抗凋亡基因 mcl1 和 bcl2 的表达，可能通过阻止多柔比星诱导的细胞凋亡导致细胞存活。另一方面，enzalutamide 可能通过下调 bid/bcl2/mcl1 轴使细胞对多柔比星敏感，而 bid/bcl2/mcl1 轴通常会激活执行半胱天冬酶，半胱天冬酶 3/7。后一种酶的活性在细胞凋亡晚期的 DNA 降解中很明显。

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Enzalutamide Overcomes Dihydrotestosterone-Induced Chemoresistance in Triple- Negative Breast Cancer Cells via Apoptosis

Background: Triple-negative breast cancer is challenging to treat due to its heterogeneity and lack of therapeutic targets. Hence, systemic chemotherapy is still the mainstay in TNBC treatment. Unfortunately, patients commonly develop chemoresistance. Androgen signalling through its receptor is an essential player in breast cancer, where it has been shown to confer chemoresistance to TNBC cells. Objective: The objective of the study was to elucidate the mechanistic effects of enzalutamide in the chemoresponse of TNBC cells to doxorubicin through the apoptosis pathway. Methods: MDA-MB-231 and MDA-MB-453 cells were used as model systems of TNBC. Cell viability and apoptosis were investigated upon treatment of cells with doxorubicin in the presence of dihydrotestosterone (DHT) and/or enzalutamide. Caspase 3/7 activity and TUNEL assays were performed to assess the induction of apoptosis. The expression of apoptosis-regulatory genes was assayed by qPCR for the detection of expression changes. Results: Enzalutamide decreased the viability of MDA-MB-231 and MDA-MB- 453 cells and reduced DHT-induced chemoresistance of both cell lines. It also increased the chemosensitivity towards doxorubicin in MDA-MB-231 cells. Increasing DNA degradation and caspase 3/7 activity were concomitant with these outcomes. Moreover, enzalutamide downregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in MDA-MB-231 cells, while increasing the expression of the pro-apoptotic gene bid. On the other hand, DHT upregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in both cell lines. Conclusion: DHT increased the expression of the anti-apoptosis genes mcl1 and bcl2 in the TNBC cells, presumably leading to cell survival via the prevention of doxorubicin-induced apoptosis. On the other hand, enzalutamide may sensitize the cells to doxorubicin through downregulation of the bid/bcl2/mcl1 axis that normally activates the executive caspases, caspase 3/7. The activities of the latter enzymes were apparent in DNA degradation at the late stages of apoptosis.

更新日期：2022-05-11

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