TY - JOUR
T1 - Sulforaphane Mediates Glutathione Depletion via Polymeric Nanoparticles to Restore Cisplatin Chemosensitivity
AU - Xu, Ying
AU - Han, Xuexiang
AU - Li, Yiye
AU - Min, Huan
AU - Zhao, Xiao
AU - Zhang, Yinlong
AU - Qi, Yingqiu
AU - Shi, Jian
AU - Qi, Sheng
AU - Bao, Yongping
AU - Nie, Guangjun
N1 - Funding Information:
This work was financially supported by National Key R&D Program of China (grant nos. 2018YFA0208900, 2016YFA0201600), National Natural Science Foundation of China (grant no. 31571021), Innovation Group of the National Natural Science Foundation of China (grant no. 11621505), Frontier Research Program of the Chinese Academy of Sciences (grant no. QYZDJ-SSW-SLH022), K.C.Wong Education Foundation (grant no. GJTD-2018-03), the Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, CAS, and an award from Cancer Prevention Research Trust (R206861), UK.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019
Y1 - 2019
N2 - Platinum (Pt)-based chemotherapy is a broadly used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to codeliver a water-soluble CDDP derivative, poly(γ,l-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to improve the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful antitumor activity. Finally, this nanoenhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nanostrategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.
AB - Platinum (Pt)-based chemotherapy is a broadly used therapeutic regimen against various cancers. However, the insufficient cellular uptake, deactivation by thiol-containing species and nonspecific distribution of cisplatin (CDDP) result in its low chemosensitivity as well as systemic side effects, which can largely constrain the employment of CDDP in clinical treatment. To circumvent these problems, in this study, polymeric nanoparticles were utilized to codeliver a water-soluble CDDP derivative, poly(γ,l-glutamic acid)-CDDP conjugate, and a naturally occurring compound derived from broccoli, sulforaphane, which can achieve efficient glutathione (GSH) depletion, to improve the accumulation of CDDP in cancer cells. Results show that compared with combinational treatment of CDDP and SFN, the nanoparticles were more effectively internalized and could significantly reduce GSH content in breast cancer cells, leading to a notable increase in DNA-bound Pt and DNA damage-induced apoptosis. Moreover, in an orthotopic breast cancer model, the nanoparticles achieved a significantly higher tumor accumulation and exhibited a more powerful antitumor activity. Finally, this nanoenhanced chemotherapy was further confirmed in a liver cancer model with high-expression of GSH. Taken together, this sulforaphane-based nanostrategy holds great promise to enhance the sensitivity and therapeutic efficacy of Pt-based chemotherapy.
KW - breast cancer
KW - cisplatin
KW - glutathione
KW - nanoparticle
KW - sulforaphane
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U2 - 10.1021/acsnano.9b07032
DO - 10.1021/acsnano.9b07032
M3 - Article
C2 - 31670945
AN - SCOPUS:85074698260
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
ER -