On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity

Kazufumi Honda, Takako Hishiki, Sohei Yamamoto, Takehiro Yamamoto, Nami Miura, Akiko Kubo, Mai Itoh, Wei Yu Chen, Masashi Takano, Tomoyuki Yoshikawa, Takahiro Kasamatsu, Shinichiro Sonoda, Hirotoshi Yoshizawa, Seigo Nakamura, Yuichiro Itai, Megumi Shiota, Daisuke Koike, Masayuki Naya, Noriyo Hayakawa, Yoshiko NaitoTomomi Matsuura, Keiko Iwaisako, Toshihiko Masui, Shinji Uemoto, Kengo Nagashima, Yoshinori Hashimoto, Tomohiro Sakuma, Osamu Matsubara, Wilber Huang, Tomoaki Ida, Takaaki Akaike, Yohei Masugi, Michiie Sakamoto, Tomoyasu Kato, Yoshinori Ino, Hiroshi Yoshida, Hitoshi Tsuda, Nobuyoshi Hiraoka, Yasuaki Kabe, Makoto Suematsu

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Article number101926
JournalRedox Biology
Publication statusPublished - 2021 May


  • 3-Mercaptopyruvate sulfotransferase
  • Ambroxol
  • Cancer stroma
  • Imaging metabolomics


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