JD enhances the anti-tumour effects of low-dose paclitaxel on gastric cancer MKN45 cells both in vitro and in vivo.
BACKGROUND
Gastric cancer is the third most common cause of cancer mortality worldwide, and paclitaxel (PTX) is one of the most widely used traditional drugs in gastric cancer therapy. However, the response to traditional therapy is limited by acquired chemo-resistance and side effects. Here, we establish a newly designed combination therapy consisting of a compound that is a structural variant of oridonin, i.e. Jesridonin (JD), and low-dose PTX for gastric cancer cells (MKN45) to investigate whether the anti-tumour activity of low-dose PTX could be enhanced when combined with JD.


METHODS
The interaction of JD and low-dose PTX was detected in MKN45 cells using the median-effect analysis method. The synergistic effect on cell viability and apoptosis was measured by MTT assay, colony formation assay, transient transfection, flow cytometry and Western blotting. The synergistic in vivo effect of JD plus low-dose PTX was evaluated in nude mouse xenograft models using H&E and TUNEL staining and Western blotting.


RESULTS
JD plus low-dose PTX showed a synergistic effect, as the combination indexes were less than 1. Additionally, a synergistic anti-proliferative and pro-apoptotic effect was detected for the combination of JD and low-dose PTX. The apoptotic mechanism induced by JD plus PTX revealed that the combination therapy synergistically activated the mitochondrial pathway.


CONCLUSIONS
Our findings suggest that JD enhances the anti-tumour effect of low-dose PTX on gastric carcinoma cancer cells in both vitro and in vivo, accompanied by activation of the mitochondrial pathway, which may present a more effective therapeutic strategy in gastric cancer treatment.
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Cong
C
Wang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Ran
R
Wang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Kairui
K
Zhou
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Saiqi
S
Wang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Junwei
J
Wang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Hongge
H
Shi
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Yinhui
Y
Dou
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Dongxiao
D
Yang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Liming
L
Chang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Xiaoli
X
Shi
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Ying
Y
Liu
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Xiaowei
X
Xu
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Xiujuan
X
Zhang
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China.
Yu
Y
Ke
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences, 100 Kexue Avenue, Zhengzhou, 450001, Henan, People's Republic of China. liuhm@zzu.edu.cn.
Hongmin
H
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; C000606573:jesridonin; D017239:Paclitaxel
Anti-tumour effect; Combination therapy; Gastric cancer; JD; Paclitaxel