TY - JOUR
T1 - On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity
AU - Honda, Kazufumi
AU - Hishiki, Takako
AU - Yamamoto, Sohei
AU - Yamamoto, Takehiro
AU - Miura, Nami
AU - Kubo, Akiko
AU - Itoh, Mai
AU - Chen, Wei Yu
AU - Takano, Masashi
AU - Yoshikawa, Tomoyuki
AU - Kasamatsu, Takahiro
AU - Sonoda, Shinichiro
AU - Yoshizawa, Hirotoshi
AU - Nakamura, Seigo
AU - Itai, Yuichiro
AU - Shiota, Megumi
AU - Koike, Daisuke
AU - Naya, Masayuki
AU - Hayakawa, Noriyo
AU - Naito, Yoshiko
AU - Matsuura, Tomomi
AU - Iwaisako, Keiko
AU - Masui, Toshihiko
AU - Uemoto, Shinji
AU - Nagashima, Kengo
AU - Hashimoto, Yoshinori
AU - Sakuma, Tomohiro
AU - Matsubara, Osamu
AU - Huang, Wilber
AU - Ida, Tomoaki
AU - Akaike, Takaaki
AU - Masugi, Yohei
AU - Sakamoto, Michiie
AU - Kato, Tomoyasu
AU - Ino, Yoshinori
AU - Yoshida, Hiroshi
AU - Tsuda, Hitoshi
AU - Hiraoka, Nobuyoshi
AU - Kabe, Yasuaki
AU - Suematsu, Makoto
N1 - Funding Information:
This work was supported by AMED-CREST (Y.K. and K.H.), a Grant-in Aid for Scientific Research (B) , and a Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (K.H.). The study of cell biology in vitro besides clinical researches was supported by Research Foundation for Opto-Science and Technology in Hamamatsu-City, Japan (T.Y.). Infrastructure of imaging MS was developed by JST ERATO Suematsu Gas Biology (2010–2015 led by M.Su.). Laser-confocal line scanning SERS was supported by AMED-CREST (led by Y.K.). The study sponsors played no role in the study design, in the collection, analysis or interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. All authors confirm that they have reviewed and agreed to the submission of this manuscript.
Funding Information:
This work was supported by Japan Agency for Medical Research and Development (AMED) which included a grant of JP201m0203004 (T.H.), AMED-CREST for Metabolism (K.H. and Y.K.). The study was also supported by a Grant-in-Aid for Scientific Research (B), and a Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (K.H.). Research Foundation for Opto-Science and Technology in Hamamatsu-City (T.Y.) supports funding for cell biology experiments. Infrastructure for metabolomics and Raman spectroscopy to determine persulfides was supported by JST ERATO Suematsu Gas Biology Project (M.S.) until March 2015. Infrastructure of laser-scanning confocal Raman spectroscopy was supported by AMED-CREST (Y.K. JP17gm0710010) and partly by JST Moonshot Program for Cancer Research from 2020.This work was supported by AMED-CREST (Y.K. and K.H.), a Grant-in Aid for Scientific Research (B), and a Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (K.H.). The study of cell biology in vitro besides clinical researches was supported by Research Foundation for Opto-Science and Technology in Hamamatsu-City, Japan (T.Y.). Infrastructure of imaging MS was developed by JST ERATO Suematsu Gas Biology (2010–2015 led by M.Su.). Laser-confocal line scanning SERS was supported by AMED-CREST (led by Y.K.). The study sponsors played no role in the study design, in the collection, analysis or interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. All authors confirm that they have reviewed and agreed to the submission of this manuscript.
Funding Information:
This work was supported by Japan Agency for Medical Research and Development (AMED) which included a grant of JP201m0203004 (T.H.), AMED-CREST for Metabolism (K.H. and Y.K.). The study was also supported by a Grant-in-Aid for Scientific Research (B), and a Challenging Exploratory Research grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (K.H.). Research Foundation for Opto-Science and Technology in Hamamatsu-City (T.Y.) supports funding for cell biology experiments. Infrastructure for metabolomics and Raman spectroscopy to determine persulfides was supported by JST ERATO Suematsu Gas Biology Project (M.S.) until March 2015. Infrastructure of laser-scanning confocal Raman spectroscopy was supported by AMED-CREST (Y.K. JP17gm0710010 ) and partly by JST Moonshot Program for Cancer Research from 2020.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - 3-Mercaptopyruvate sulfotransferase
KW - Ambroxol
KW - Cancer stroma
KW - Imaging metabolomics
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U2 - 10.1016/j.redox.2021.101926
DO - 10.1016/j.redox.2021.101926
M3 - Article
C2 - 33752108
AN - SCOPUS:85102867706
SN - 2213-2317
VL - 41
JO - Redox Biology
JF - Redox Biology
M1 - 101926
ER -
