Withaferin A Exerts Cytotoxicity in Single/Multidrug-Resistant Gastric and Ovarian Cancer Cells and Tumor Xenografts Through the AKT-NF-κB-STAT3-Survivin Axis.

IF 3.2 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Priti S Shenoy, Shubhankar Dash, Diksha Joshi, Bharat Rekhi, Vikram Gota, Pritha Ray
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引用次数: 0

Abstract

Resistance to primary chemotherapeutics poses a significant challenge in treating solid tumors. The majority of the second-line chemo and targeted therapeutics act moderately/less effectively in drug-resistant tumors owing to the multicausal nature of drug resistance. Therefore, a single agent with pleiotropic effects would be beneficial in combating this adversity. Withania somnifera exhibits multifunctional anticancer properties, but its role in overcoming chemoresistance remains poorly understood. We evaluated the cytotoxic effect of AshwamaxTM-W. somnifera (WS)-extract and Withaferin A (WFA), in intrinsically resistant (KATO-III and SKOV3) and acquired chemoresistant gastric (AGS5FU) and ovarian (A2780LR) cancer cellular models. We examined their impact on autophagy and apoptosis pathways and elucidated the underlying molecular mechanism. In vivo efficacy of WFA on cisplatin-paclitaxel-resistant epithelial ovarian cancer (EOC) xenografts was assessed using noninvasive optical imaging. Mechanistically, WFA is more proficient in targeting chemoresistant cells than AshwamaxTM-WS extract and activates apoptosis by overriding the AKT-NF-κB-STAT3-survivin axis. Preclinical imaging revealed dose-dependent tumor regression (during and after treatment) in platinum-taxol-resistant EOC xenografts that were unresponsive to cisplatin challenge. WFA, at 3 mg kg-1 dosage, reduced tumor volume by 4.7-fold compared to controls, with sustained antitumor effects persisting after treatment cessation. WFA effectively targets the AKT-NF-κB-STAT3-survivin axis to overcome single and multidrug resistance in gastric and epithelial ovarian cancers, presenting a promising therapeutic alternative for chemoresistant malignancies.

Withaferin A通过AKT-NF-κB-STAT3-Survivin轴对单药/多药耐药胃癌和卵巢癌细胞及肿瘤异种移植物施加细胞毒性。
原发性化疗药物的耐药性是实体瘤治疗的一个重大挑战。由于耐药的多因果性,大多数二线化疗和靶向治疗对耐药肿瘤的作用一般或较差。因此,一种具有多效性的单一药剂将有利于对抗这种逆境。Withania somnifera显示出多功能抗癌特性,但其在克服化学耐药中的作用仍然知之甚少。我们评价了AshwamaxTM-W的细胞毒作用。somnifera (WS)提取物和Withaferin A (WFA)在内在耐药(KATO-III和SKOV3)和获得性化疗耐药胃(AGS5FU)和卵巢癌(A2780LR)细胞模型中的作用。我们研究了它们对自噬和凋亡途径的影响,并阐明了潜在的分子机制。采用无创光学成像技术评估WFA对顺铂-紫杉醇耐药上皮性卵巢癌(EOC)异种移植的体内疗效。在机制上,WFA比AshwamaxTM-WS提取物更擅长靶向化疗耐药细胞,并通过覆盖AKT-NF-κB-STAT3-survivin轴激活细胞凋亡。临床前影像学显示,对顺铂无反应的铂-紫杉醇耐药EOC异种移植物的肿瘤消退(治疗期间和治疗后)呈剂量依赖性。WFA在3mg kg-1剂量下,与对照组相比,肿瘤体积减少了4.7倍,在治疗停止后持续的抗肿瘤作用持续存在。WFA有效靶向AKT-NF-κB-STAT3-survivin轴,克服胃癌和上皮性卵巢癌的单药和多药耐药,为化疗耐药恶性肿瘤提供了一种有希望的治疗选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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