Wei Zheng1, Chun-Yan Zhou2, Xin-Qing Zhu1, Xue-Jian Wang1, Zi-Yao Li1, Xiao-Chi Chen1, Feng Chen1, Xiang-Yu Che3, Xin Xie4. 1. Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. 2. Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. 3. Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. Electronic address: dalianchexiangyu@163.com. 4. Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. Electronic address: xiexin_phd@163.com.
Abstract
BACKGROUND: 5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. METHODS: 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. RESULTS: 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. CONCLUSION: Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment.
BACKGROUND:5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. METHODS: 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. RESULTS:5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. CONCLUSION:Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment.
Authors: Essa M Bajalia; Farah B Azzouz; Danielle A Chism; Derrek M Giansiracusa; Carina G Wong; Kristina N Plaskett; Anupam Bishayee Journal: Cancers (Basel) Date: 2022-07-04 Impact factor: 6.575
Authors: Leonid N Maslov; Sergey V Popov; Natalia V Naryzhnaya; Alexandr V Mukhomedzyanov; Boris K Kurbatov; Ivan A Derkachev; Alla A Boshchenko; Igor Khaliulin; N Rajendra Prasad; Nirmal Singh; Alexei Degterev; Evgenia A Tomilova; Ekaterina V Sapozhenkova Journal: Apoptosis Date: 2022-08-20 Impact factor: 5.561