Posaconazole attenuates arsenic trioxide toxicity and enhances safety and efficacy while reducing invasion and metastasis in non-small-cell lung cancer.

The clinical use of the anti-cancer drug arsenic trioxide (ATO) has been limited due to its side effects and the development of cancer cell resistance, highlighting the need for combination therapy. In this study, we optimized and characterized the combination of antifungal drug posaconazole (PCZ) and ATO in A549 lung cancer cells using single-drug monotherapy and sequential/pretreatment combination assays. In the pretreatment approach, the cells were incubated with PCZ for 6 h, followed by incubation with ATO for 48 h. MTT assay indicated that the sequential (pretreatment) combination of ATO and PCZ produced an IC50 value of 25 μmol/L, whereas PCZ and ATO alone exhibited IC50 values of 100 μmol/L and 75 μmol/L, respectively. qRT-PCR analysis showed that treatment at the IC50 concentration of ATO upregulated HMGA2 and Bcl-2 gene expression, while the combination of ATO with PCZ significantly countered these effects. Additionally, overexpression of HMGA2, VEGF, and MMP-9 indicated a high potential for invasion and metastasis, particularly at 75 μmol/L ATO, as demonstrated by wound healing and transwell invasion assays. In contrast, the pretreatment combination showed high efficacy in inducing cytotoxicity in lung cancer cells with minimal risk of invasion and metastasis. The results indicated that this enhanced cytotoxicity occurs through apoptosis induction and modulation of the Hedgehog signaling pathway via targeting SMO and Gli1. Furthermore, flow cytometry and colony formation assays revealed that PCZ attenuates and reduces the apoptotic/necrotic effects of ATO. In conclusion, PCZ synergistically and effectively reduces the adverse cytotoxic effects of ATO in lung cancer cells, providing a promising new therapeutic strategy for lung cancer treatment.