Dual target effect of hemiprotonic phenoline-phenoline+ on inhibiting metastatic breast cancer and concurrent candidiasis

Abstract

Abstract Background Metastatic breast cancer is a challenge in clinical, and the frequent occurrence of concurrent infections in patients is a direct cause of patient death. However, there is no effective treatment to improve the survival rate and extend the survival period. Here we propose a dual target strategy to treat the cancer and concurrent candidiasis. Since hemiprotonic dimers generally have high biological activity, a chemical called hemiprotonic phenoline-phenoline+ (ph-ph+) was used in the study to explore the feasibility of dual target effect of anticancer and antifungus. Methods The metastasis of breast cancer cells were detected by transwell migration and invasion assay, as well as cell scratch assay. The fungicidal effect of ph-ph+ was evaluated by MIC and MFC. The targets were identified by pPLAGL2 transfection and caseinolytic peptidase P (CLpP) activity determination. The animal model of experimental metastatic breast cancer combined with candidiasis was prepared to prove the anticancer and antifungal effect. Results The results showed that ph-ph+ could suppress the proliferation and metastasis of breast cancer cells, and meanwhile kill Candida albicans (C. albicans) effectively. The mechanism of antifungus and anticancer of ph-ph+ was associated with the activation of an evolutionarily conserved protease CLpP. Also, ph-ph+ could inhibit the signaling pathway mediated by PLAGL2 that highly expressed in cancer cells, thereby participating in preventing cell metastasis and inducing apoptosis. In experimental animal model, ph-ph+ retarded the growth and metastasis of the cancer cells, and eliminate C. albicans in tissues at the same time. Conclusions The result suggests that CLpP and PLAGL2 as dual targets could be an potential approach against metastatic cancer and pathogenic fungus, and identifies the effectiveness of ph-ph+ as the dual target inhibitor.