On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity.
On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity.
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DOI：
10.1016/j.redox.2021.101926
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Suematsu M
中科院分区：
文献类型：
--
作者：
Honda K;Hishiki T;Yamamoto S;Yamamoto T;Miura N;Kubo A;Itoh M;Chen WY;Takano M;Yoshikawa T;Kasamatsu T;Sonoda S;Yoshizawa H;Nakamura S;Itai Y;Shiota M;Koike D;Naya M;Hayakawa N;Naito Y;Matsuura T;Iwaisako K;Masui T;Uemoto S;Nagashima K;Hashimoto Y;Sakuma T;Matsubara O;Huang W;Ida T;Akaike T;Masugi Y;Sakamoto M;Kato T;Ino Y;Yoshida H;Tsuda H;Hiraoka N;Kabe Y;Suematsu M
对顺铂衍生物的化学敏感性在包括卵巢癌在内的难治性恶性肿瘤的个体患者中各不相同，而如何解锁耐药性仍然未知。在发现-（n = 135）和验证-（n = 47）队列中，卵巢癌组织在减瘤手术中收集，以使用高通量自动化免疫组织化学进行分析，该免疫组织化学鉴定胱硫醚γ-裂解酶（CSE）作为区分术后基于铂的化疗的无应答者与应答者的独立标志物。我们的目的是确定CSE衍生的代谢物负责的化学耐药机制：金纳米粒子（AuN）的表面增强拉曼光谱（Sers）被用来增强电磁场，这使得能够可视化多种含硫代谢物通过检测散射光从Au-S振动二维。透明细胞癌（CCC）对顺铂的敏感性低于浆液性腺癌，根据480 cm−1处的Sers强度分为两组;强度较大的患者在减瘤手术后的总生存期较短。Sers信号通过局部应用的单溴双丙烷（monobromobimane）消除，该单溴双丙烷断裂多硫化物的硫烷-硫键，导致在580 cm-1处检测到的磺基双丙烷的形成，表明癌组织中多硫化物的存在。培养中的CCC衍生癌细胞系对顺铂具有耐药性，但用氨溴索（一种降解多硫化物的祛痰剂）治疗使细胞对CDDP敏感。氨溴索与顺铂联合给药可显著抑制裸鼠体内异种移植瘤的生长。此外，多硫化物，但既不是谷胱甘肽也不是亚牛磺酸，衰减顺铂诱导的DNA超螺旋的干扰。因此，通过组织上Sers的多硫化物检测能够预测基于顺铂的化疗的预后。目前的研究结果表明，多硫化物降解作为一种策略解锁顺铂耐药性。胱硫醚-γ-裂解酶预测卵巢癌术后化疗耐药Sers可视化组织上的多硫化物对化疗无反应。多硫化物改善顺铂诱导的DNA损伤以阻断癌细胞死亡。氨溴索降解多硫化物以解除体外和体内的化疗耐药性。
Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm−1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm−1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance. Cystathionine-γ-lyase predicts post-operative chemoresistance in ovarian cancer. SERS visualizes on-tissue polysulfides in non-responders against chemotherapy. Polysulfides ameliorate cisplatin-induced DNA damages to block cancer cell death. Ambroxol degrades polysulfides to unlock chemoresistance in vitro and in vivo.
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