Selective Antitumor Effect and Lower Toxicity of Mitochondrion-Targeting Derivatization of Triptolide.

Triptolide has a significant antitumor activity, but its toxicity limits its clinical application. As the mitochondrion-targeting strategy showed an advantage in selective antitumor effect based on the higher mitochondrial membrane potential (MMP) in tumor cells than normal cells, the lipophilic cations triphenylphosphonium and E-4-(1H-indol-3-yl vinyl)-N-methylpyridinium iodide (F16) were selected as targeting carriers for structural modification of triptolide. The derivatives bearing F16 generally retained most antitumor activities, overcame its inhibition plateau phenomena, and enhanced its selective antitumor effect in lung cancer. The representative derivative F9 could accumulate in the mitochondria of NCI-H1975 cells, inducing apoptosis and a dose-dependent increase in intracellular reactive oxygen species and reducing MMP. Moreover, no effects were observed in normal cells BEAS-2B. In vivo studies showed that the developmental, renal, and liver toxicities of F9 to zebrafish were significantly lower than those of triptolide. This study provides a promising idea to relieve the toxicity problem of triptolide.

Synergistic effect of eravacycline combined with fluconazole against resistant Candida albicans in vitro and in vivo.

BACKGROUND: The limited availability of antifungal drugs for candidiasis and the persistent problem of drug resistance, necessitates the urgent development of new antifungal drugs and alternative treatment options. RESEARCH DESIGN AND METHODS: This study examined the synergistic antifungal activity of the combination of eravacycline (ERV) and fluconazole (FLC) both in vitro by microdilution checkerboard assay and in vivo by Galleria mellonella model. The underlying synergistic mechanisms of this drug combination was investigated using RNA-sequencing and qPCR. RESULTS: ERV (2 µg/mL) + FLC (0.25-0.5 µg/mL) had strong synergistic antifungal activity against resistant Candida albicans (C. albicans) in vitro, as evidenced by a fractional inhibitory concentration index of 0.0044-0.0088. In vivo experiments in Galleria mellonella larvae infected with resistant C. albicans revealed that ERV (2 µg/larva) + FLC (1 µg/larva) improved survival rates and reduced fungal burden. The results of RNA-sequencing and qPCR showed that the mechanism of synergistic inhibition on resistant C. albicans was related to the inhibition of DNA replication and cell meiosis. CONCLUSIONS: These results indicate that the combination of ERV and FLC effectively inhibits resistant C. albicans both in vitro and in vivo and lay the foundation for a potential novel treatment option for candidiasis.

Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier.

Based on the higher mitochondrial membrane potential (Δψm) of tumor cells than normal cells, a mitochondria-targeting strategy using delocalized lipophilic cations as carriers is a promising way to improve the antitumor effect of small molecules and to reduce toxicity. Triptolide (TP) has a strong antitumor effect but is limited in the clinic due to high systemic toxicity. Mitochondria-targeted TP derivatives were designed and synthesized using triphenylphosphine cations as carriers. The optimal derivative not only maintained the antitumor activity of TP but also showed a tumor cell selectivity trend. Moreover, the optimal derivative increased the release of lactate dehydrogenase and the production of ROS, decreased Δψm, and arrested HepG2 cells in G0/G1 phase. In a zebrafish HepG2 xenograft tumor model, the inhibitory effect of the optimal derivative was comparable to that of TP, while it had no obvious toxic effect on multiple indicators in zebrafish at the test concentrations. This work provided some evidence to support the mitochondria-targeting strategy.