通过阻断巯基酸途径转运体提高卵巢癌细胞对卡铂的敏感性

IF 3.3 3区 医学 Q2 ONCOLOGY
B Madhu Krishna, Sravani K Ramisetty, Pankaj Garg, Atish Mohanty, Edward Wang, David Horne, Sanjay Awasthi, Prakash Kulkarni, Ravi Salgia, Sharad S Singhal
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引用次数: 0

摘要

RLIP 是一种转运体,能对压力做出反应并提供保护,特别是针对谷胱甘肽-亲电子共轭物和异生物毒素。在恶性细胞中,尤其是在癌症细胞中,RLIP 的存在越来越多,这凸显了它至关重要的抗凋亡功能。这是通过选择性地调节细胞中促凋亡氧化脂质副产物的水平来实现的。通过有效抑制巯基酸途径中的转运体 RLIP,可以抑制人体异种移植中肿瘤的发展,而无需进行化疗。我们利用卵巢癌(OC)细胞系(MDAH2774、OVCAR4 和 OVCAR8)观察到,靶向 RLIP 的药物,如 RLIP 反义和 RLIP 抗体,不仅大大降低了 OC 细胞的活力,还显著提高了它们对卡铂的敏感性。为了进一步研究 RLIP 反义、RLIP 抗体和卡铂之间的细胞毒性协同作用,我们在细胞培养和异种移植的 OC 细胞中进行了研究。研究结果表明,通过硫代磷酸酯反义抑制 RLIP 可使已建立的皮下人类卵巢异种移植物快速、持续地缓解病情。此外,通过 RLIP 抗体抑制 RLIP 与反义的疗效相当,并提高了卡铂对 MDAH2774 卵巢癌异种移植物的疗效。这些研究强调,RLIP是支持癌细胞存活的关键核心载体,因此适合作为癌症治疗的重点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhancing carboplatin sensitivity in ovarian cancer cells by blocking the mercapturic acid pathway transporter.

Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione-electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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