Development of 10-Hydroxycamptothecin-crizotinib conjugate based on the synergistic effect on lung cancer cells.

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

Prediction of the mechanisms of action of Zhibai Dihaung Granule in cisplatin-induced acute kidney injury: A network pharmacology study and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhibai Dihuang Granule (ZDG) is known as traditional Chinese patent medicine with the functions of "Ziyin decrease internal heat" in Traditional Chinses medicine. In clinical, it is also used to treat various kidney diseases. AIM OF THE STUDY: We aimed to provide a basis for the curative effect of ZDG on acute kidney injury induced by cisplatin (CIAKI). MATERIALS AND METHODS: The active compounds and protein targets of ZDG, as well as the potential targets of the CIAKI were searched from the database. The protein-protein interaction (PPI) network diagram and the drug-compounds-targets-disease network were constructed. Enrichment analysis was performed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, the effect of ZDG on the prevention and treatment of CIAKI was experimentally validated in vivo and in vitro. RESULTS: From the database, we screened 22 active compounds of ZDG and 226 related targets. We obtained 498 gene targets related to CIAKI, among which 40 genes overlapped with ZDG-related targets. Go enrichment and KEGG analysis got 339 terms and 64 pathways, respectively. Based on the above study, we speculated that ZDG has the potential effect on treatment CIAKI, and the mechanism may be related to cell apoptosis and inflammation. The results in vitro experiments showed that ZDG reduced the cytotoxicity of cisplatin to HK-2 and 293T cells, but did not affect the antitumor effect of cisplatin. Moreover, in vivo experiments further proved that ZDG effectively controlled kidney damage caused by cisplatin in SD rats. The results showed that ZDG could regulate the expression of CASP3, p65 and MAPK pathway related proteins, suggesting that ZDG's prevention of CIAKI may be related to apoptosis and inflammatory response. CONCLUSIONS: Our study showed that ZDG could prevent and treat CIAKI by inhibiting cell apoptosis and inflammation, which provided a new efficacy and clinical application for ZDG.