Cancer cell cytotoxicity in mitochondria localized N-Alkyltriphenylvinylpyridinium Artemisinin

Targeted drug design aimed at decreasing toxicity to normal cells and enhancing anticancer activity has received considerable attention in recent years. Repurposing FDA-approved drugs (e.g., Dihydroartemisinin; DHA for antimalaria) due to toxicity to cancer cells and relatively no toxicity to normal cells has emerged as a promising approach for cancer therapy. Many diseases, including cancer, are associated with dysfunctionality of mitochondria. Developing probes for visualization of mitochondria may offer insight into cancer cell mitochondria function and mechanisms of drug resistance. The hypothesis of this work is that DHA targeted to cancer cell will exhibit increased versus normal cells. Fluorescent mitochondria-targeted dihydroartemisinin derivatives were prepared by attachment to triphenylvinylpyridinium (TPVP) cations with cleavable amide linkers. TPVP-DHA showed significantly higher anticancer activity against melanoma A375 and pancreatic cancer MiaPaCa-2 cell lines compared to DHA alone, whereas human normal fibroblasts were immune to this treatment. Mitochondria-specific accumulation of TPVP-DHA in melanoma A375 with fluorescence turn-on was observed using confocal fluorescence microscopy. Our results demonstrate that targeting of FDA-approved DHA to mitochondria induces metabolic oxidative stress by inhibiting the mTOR and ERK1/2 signaling pathways that resulted in a G₁-delay and enhanced toxicity of cancer cells. In summary, TPVP-DHA is advanced as a novel anti-cancer small molecule and a potentially valuable adjuvant to cancer therapy.