Cancer Management and Research (Dec 2020)
Pyrrolidine Dithiocarbamate Facilitates Arsenic Trioxide Against Pancreatic Cancer via Perturbing Ubiquitin-Proteasome Pathway
Abstract
Simin Yu,1,* Ning Wu,2,* Jianmin Zhu,3 Ying Liu,4 Jinbin Han1 1Department of Traditional Chinese Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Pudong New Area Gongli Hospital, Shanghai, People’s Republic of China; 3Shanghai Clinical Center, Chinese Academy of Sciences/Xuhui Central Hospital, Shanghai, People’s Republic of China; 4Department of Oncology, Yunnan Provincial Hospital of Chinese Medicine, Kunming, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinbin Han Tel +862123271699Fax +862163136856Email [email protected]: To investigate whether pyrrolidine dithiocarbamate (PDTC) could facilitate arsenic trioxide (ATO) to induce apoptosis in pancreatic cancer cells via perturbing ubiquitin-proteasome pathway.Methods: Mass spectrometry was performed to examine the interaction between PDTC and ATO, and the data showed they could form a complex termed PDTC-ATO. Inhibiting effects on cell viability were examined by CCK-8 test, and apoptosis was examined by flow cytometry. Four treatment arms (n = 6), including the control, PDTC, ATO, and PDTC-ATO, were evaluated using BALB/c nude mouse models bearing a xenograft tumor of SW1990 human pancreatic cancer line. Western blot, immunohistochemistry assays were to detect the mechanism.Results: The results showed that PDTC-ATO had higher inhibiting effects on proliferation of pancreatic cancer cells than ATO in vitro. In bearing-tumor mice, PDTC-ATO inhibited tumor growth by 79%, being more potent than ATO (by 46%) or PDTC (by 35%) compared to the control. Results of Western blot and immunohistochemistry showed proteasome inhibition and apoptotic cell death, together with obvious suppression of associating E3 ubiquitin ligase activity, occurred more frequently in tumors treated with PDTC-ATO than those with ATO.Conclusion: PDTC demonstrated the function to facilitate ATO against pancreatic cancer due to forming a stable complex to perturb ubiquitin-proteasome pathway.Keywords: arsenite, ubiquitin ligase, pancreatic cancer cell, dithiocarbamate, complex
