Novel dihydroartemisinin derivative Mito-DHA5 induces apoptosis associated with mitochondrial pathway in bladder cancer cells

Abstract

Background Bladder cancer is the second most common genitourinary malignancy and the eleventh most common cancer worldwide. Dihydroartemisinin (DHA), a first-line antimalarial drug, has been found to have potent antitumor activity. In our previous study, a novel dihydroartemisinin derivative Mito-DHA5 synthesized in our laboratory has a stronger anti-tumor activity than DHA. In this study, we investigated the apoptotic effect of Mito-DHA5 on bladder cancer T24 cells and molecular mechanisms underlying. Methods Antitumor activity in vitro was evaluated by MTT, wound healing and cloning formation assays. Mitochondrial membrane potential (MMP) was detected by JC-1 probe and ROS levels were measured by specific kit. The expression of caspase-3, cleaved-caspase3, mitochondrial Cyt-C, Bcl-2, Bax and PARP in T24 cells was evaluated by Western blotting. Results The results showed that Mito-DHA5 reduced cell viability with an IC50 value of 3.2 µM and induced T24 cell apoptosis in a dose-dependent manner, increased the production of ROS and decreased MMP. Mito-DHA5 could down-regulate the expression of Bcl-2, mitochondrial Cyt-C, Caspase-3, PARP and up-regulate the expression of Bax and cleaved Caspase-3. Conclusions These data suggested that Mito-DHA5 had a potent inhibitory effect on T24 bladder cancer cell growth and induced these cells apoptosis associated with mitochondrial pathway.

Synthesis and Antitumor Activities of Novel Mitochondria-Targeted Dihydroartemisinin Ether Derivatives

“…Among these compounds, D8-T had potent antitumor activity against all tested cell lines with greatest selectivity (Selectivity index = IC 50(HUVEC) /IC 50(T24) = 4.4) against the T24 cell line. Compared with DHA, the antitumor activity of D8-T against T24 cells increased 1256.6 times. Therefore, D8-T was selected for further pharmacological mechanism studies in T24 and J82 cells.…”

“… a The data are from ref ( 15 ) and the unit was μM. b The data are from ref ( 14 ) and the unit was μM. NT: no test.…”

“…The antitumor mechanism of DHA includes inhibition of proliferation, induction of apoptosis and ferroptosis, , and autophagy . However, in our previous study, we found that DHA displayed antitumor activity in a relatively high dose at a micromolar level. − Furthermore, high dosage of DHA causes neurotoxicity, largely limiting its clinical antitumor application. , Thus, there is an urgent need to find novel DHA derivatives with higher antitumor activity to satisfy their clinical transformation.…”

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis, Anticancer Activity and Docking Simulation

“…Bcl-2 family proteins regulate the apoptosis pathway of mitochondria. The latter takes mitochondrial depolarization as a starting point, which is regulated by members of the Bcl-2 protein family, followed by the release of the apoptosis signal [ 42 ]. The substantial mitochondria apoptotic pathway is induced by various types of non-receptor-mediated stimuli which generate intracellular signals that target the cell apoptosis.…”