br induced MPTP opening may be
induced MPTP opening may be related with the reaction of DN3 with the cysteine203 residue of CypD, further research is needed, however. Inaddition, recent studies have indicated that the anti-tumor effect of some ent-kaurane diterpenes is associated with p53 activation (Ma et al., 2013; Li et al., 2012), next we will also perform experiments to confirm whether DN3-induced MPTP opening via CypD is related to p53.
In conclusion, this study demonstrate that DN3 selectively kills human gastric cancer Tadalafil via acting directly on mitochondria in a PTPC-mediated manner, which provides evidence that DN3, a synthetic analog of natural ent-kaurane diterpene, constitutes a new group of selective anticancer agents targeting mitochondria.
Conflict of interest
There are no conflicts of interest to declare.
Fig. 8. PTPC inhibitors prevent the cytotoxic effects of DN3 in HGC-27 cells. Cells were pretreated with or without the known VDAC1 inhibitor DIDS and/or CypD inhibitor CsA for 1 h, then exposed to 8 μM DN3 or indicated doses for 24 h. The cells were stained with FITC-annexin V/PI and then analyzed by flow cytometry (A). (B) The bar graphs show that PTPC inhibitors prevent the apoptosis rates of HGC-27 cells caused by DN3. Data were expressed as means ± S.D., n = 3. (C) The cells were lysed in lysis buffer, the expression of VDAC1 and CypD was measured by western blot, GAPDH were used as loading controls. (D) HGC-27 cells were pretreated with or without PTPC inhibitors for 1 h, and then incubated with the indicated concentrations of DN3 for 24 h. Cell viabilities were evaluated by MTT assay. Data were expressed as means ± S.D. Each data point was an average of three independent experiments. **P < 0.01 as compared with control; ##P < 0.01, DN3 versus DN3 + PTPC inhibitors.
graft tumor growth in nude mice. (A)
Photographs of tumors in vehicle group
nificantly decreased tumor size (B) and
tumor weight (C) compared with the
vehicle control. (D) Mouse body weight
was not significantly affected by DN3.
Data are presented as means ± S.D.
sidered statistically significant com-
pared with the vehicle control.
CRediT authorship contribution statement
Yong-Cheng Ma: Conceptualization, Funding acquisition, Writing -
original draft. Ying-Li Zhu: Methodology. Nan Su: Methodology.
Yu Ke: Conceptualization. Xia-Xia Fan: Methodology. Xiao-Jing Shi:
Methodology. Hong-Min Liu: Conceptualization, Funding acquisition.
Ai-Feng Wang: Project administration.
This work was financially supported by the National Natural Science Foundation of China (no. 81502952), Key Science and Technology Program of Henan Province and Medical Science, Technology Key Research Program of Henan Province (no. 2018020462), and Zhengzhou University People's Hospital "23456 Talent Engineering Fund" (3 Period).
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