Inecalcitol

The use of tyrosine kinase inhibitors (TKIs) as a treatment for chronic myeloid leukemia (CML) has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has antiproliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the 14-epi-analogue of Calcitriol (1,25(OH)₂-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells.

The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line.

Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI₅₀ values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI₅₀ values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). Furthermore, the combination treatments showed synergistic interaction between the antileukemic drugs and Inecalcitol, with combination indices (CI) < 1.

The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML.

Many vitamin D analogs and sterols-related compounds have been identified and extracted from several plants including Solanaceae species. The aim of our study was to evaluate the antifungal potential of 15 vitamin D, D3 analogs, and some sterols-related compounds that have been detected in some plants along with 3 standard antifungal drugs, Isavuconazole, Fluconazole, and Voriconazole, on the Mucormycosis-sterol 14-alpha demethylase (CYP51) enzyme by in silico study.

In this work, the molecular simulation was used to prepare the specific enzyme and the antifungal profiles utilized for the molecular docking of the contemplated compounds and subsequent prediction for the mechanism of binding within the catalytic site of Sterol 14-Demethylase (CYP51) to speculate their binding affinities. Anti-fungal medications, Fluconazole and Voriconazole revealed drugs bound distant from the binding sites, but Isavuconazole bound close to the binding site. In this context, the 15 vitamin D and D3 compounds were somewhat seen in binding proximity, especially for Alfacalcidol, Eldecalcitol, and Inecalcitol.

Seocalcitol and Isavuconazole had the lowest binding energies and were the closest ones connected to the binding cavities with the best binding free energies equal −13.21 ± 0.24 and −15.29 ± 0.25, respectively.

Isavuconazole and Seocalcitol could potentially be further assessed to be adjuvantly used as drugs to inhibit the fungal activity by targeting CYP51, a significant target for anti-fungal as well as anti-protozoan drugs, and hence could be efficient against mucormycosis.