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 Naito; Tomomi 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

doi:10.1016/j.redox.2021.101926

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

Redox Biol. 2021 May:41:101926. doi: 10.1016/j.redox.2021.101926. Epub 2021 Mar 2.

Authors

Kazufumi Honda¹, Takako Hishiki², Sohei Yamamoto³, Takehiro Yamamoto², Nami Miura⁴, Akiko Kubo², Mai Itoh², Wei-Yu Chen⁵, Masashi Takano⁶, Tomoyuki Yoshikawa⁷, Takahiro Kasamatsu⁸, Shinichiro Sonoda⁹, Hirotoshi Yoshizawa⁹, Seigo Nakamura⁹, Yuichiro Itai⁹, Megumi Shiota⁹, Daisuke Koike¹⁰, Masayuki Naya⁹, Noriyo Hayakawa², Yoshiko Naito², Tomomi Matsuura², Keiko Iwaisako¹¹, Toshihiko Masui¹², Shinji Uemoto¹², Kengo Nagashima¹³, Yoshinori Hashimoto¹⁴, Tomohiro Sakuma¹⁵, Osamu Matsubara¹⁶, Wilber Huang¹⁷, Tomoaki Ida¹⁸, Takaaki Akaike¹⁸, Yohei Masugi¹⁹, Michiie Sakamoto¹⁹, Tomoyasu Kato²⁰, Yoshinori Ino²¹, Hiroshi Yoshida²², Hitoshi Tsuda²³, Nobuyoshi Hiraoka²⁴, Yasuaki Kabe²⁵, Makoto Suematsu²⁶

Affiliations

¹ 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.
² Department Biochemistry, Keio University School of Medicine, Tokyo, Japan.
³ Department of Diagnostic Pathology, Anjo Kosei Hospital, Aichi, Japan.
⁴ Department of Biomarkers for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan; Department of Bioregulation, Graduate School of Medicine, Nippon Medical School, Japan.
⁵ Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
⁶ Department of Obstetrics and Gynecology, National Defense Medical College, Saitama, Japan.
⁷ Department of Clinical Oncology, National Defense Medical College Hospital, Saitama, Japan.
⁸ Department of Obstetrics and Gynecology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
⁹ Frontier Core Technology Laboratories, R&D Management Headquarters, FUJIFILM Corporation, Ashigara-gun, Kanagawa, Japan.
¹⁰ FUJIFILM Business Expert Corporation, Ashigara-gun, Kanagawa, Japan.
¹¹ Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, 54 Shogoin kawaracho, Sakyo, Kyoto, Japan; Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tatara Miyakodani, Kyotanabe city, Kyoto, Japan.
¹² Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, 54 Shogoin kawaracho, Sakyo, Kyoto, Japan.
¹³ Research Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tokyo, Japan.
¹⁴ Scientific Imaging Scanner Department, System Division, Hamamatsu Photonics, Hamamatsu, Japan.
¹⁵ Bioscience Division, Mitsui Knowledge Industry Corporation, Ltd., Tokyo, Japan.
¹⁶ Department of Pathology, Hiratsuka Kyosai Hospital, The Cancer Institute, Kanagawa, Japan.
¹⁷ Abnova Corporation, Taipei, Taiwan.
¹⁸ Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹⁹ Department of Pathology, Keio University School of Medicine, Japan.
²⁰ Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
²¹ Division of Molecular Pathology, National Cancer Center Research Institute, Japan.
²² Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
²³ Department of Basic Pathology, National Defense Medical College, Saitama, Japan.
²⁴ Division of Molecular Pathology, National Cancer Center Research Institute, Japan; Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
²⁵ Department Biochemistry, Keio University School of Medicine, Tokyo, Japan; AMED-CREST, Japan Agency for Medical Research and Development (AMED), Japan.
²⁶ Department Biochemistry, Keio University School of Medicine, Tokyo, Japan. Electronic address: gasbiology@keio.jp.

Abstract

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.

Keywords: 3-Mercaptopyruvate sulfotransferase; Ambroxol; Cancer stroma; Imaging metabolomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cisplatin
Drug Resistance, Neoplasm
Female
Humans
Mice
Mice, Nude
Ovarian Neoplasms* / drug therapy
Spectrum Analysis, Raman
Sulfides

Substances

Antineoplastic Agents
Sulfides
polysulfide
Cisplatin