Honda Kazufumi, Hishiki Takako, Yamamoto Sohei, Yamamoto Takehiro, Miura Nami, Kubo Akiko, Itoh Mai, Chen Wei-Yu, Takano Masashi, Yoshikawa Tomoyuki, Kasamatsu Takahiro, Sonoda Shinichiro, Yoshizawa Hirotoshi, Nakamura Seigo, Itai Yuichiro, Shiota Megumi, Koike Daisuke, Naya Masayuki, Hayakawa Noriyo, Naito Yoshiko, Matsuura Tomomi, Iwaisako Keiko, Masui Toshihiko, Uemoto Shinji, Nagashima Kengo, Hashimoto Yoshinori, Sakuma Tomohiro, Matsubara Osamu, Huang Wilber, Ida Tomoaki, Akaike Takaaki, Masugi Yohei, Sakamoto Michiie, Kato Tomoyasu, Ino Yoshinori, Yoshida Hiroshi, Tsuda Hitoshi, Hiraoka Nobuyoshi, Kabe Yasuaki, Suematsu Makoto
Department of Biomarkers for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Japan; Department of Bioregulation, Graduate School of Medicine, Nippon Medical School, Japan.
Department Biochemistry, Keio University School of Medicine, Tokyo, Japan.
Redox Biol. 2021 May;41:101926. doi: 10.1016/j.redox.2021.101926. Epub 2021 Mar 2.
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; 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, 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.
包括卵巢癌在内的难治性恶性肿瘤患者对顺铂衍生物的化学敏感性存在个体差异，而如何克服耐药性仍不清楚。在发现队列（n = 135）和验证队列（n = 47）中，收集了减瘤手术中的卵巢癌组织，并用高通量自动免疫组织化学进行分析，该方法将胱硫醚γ-裂解酶（CSE）鉴定为区分术后铂类化疗无反应者和有反应者的独立标志物。我们旨在确定负责化疗耐药机制的CSE衍生代谢物：基于金纳米颗粒（AuN）的表面增强拉曼光谱（SERS）用于增强电磁场，通过二维检测来自Au-S振动的散射光，能够可视化多种含硫代谢物。结果显示，透明细胞癌（CCC）对顺铂的敏感性低于浆液性腺癌，根据480 cm处SERS强度的大小分为两组；强度较大的患者在减瘤手术后的总生存期较短。通过局部应用单溴双硫仑消除SERS信号，单溴双硫仑可破坏多硫化物的硫烷硫键，导致形成在580 cm处检测到的磺基双硫仑二聚体，表明癌组织中存在多硫化物。培养的CCC来源的癌细胞系对顺铂耐药，但用氨溴索（一种降解多硫化物的祛痰剂）处理可使细胞对顺铂敏感。氨溴索与顺铂联合给药显著抑制了裸鼠体内癌异种移植瘤的生长。此外，多硫化物而非谷胱甘肽或亚牛磺酸减弱了顺铂诱导的DNA超螺旋紊乱。因此，通过组织上的SERS检测多硫化物能够预测基于顺铂化疗的预后。目前的研究结果表明，多硫化物降解是一种克服顺铂化疗耐药性的策略。
