N-alkyl triphenylvinylpyridinium conjugated dihydroartemisinin perturbs mitochondrial functions resulting in enhanced cancer versus normal cell toxicity

Dihydroartemisinin (DHA) is an FDA-approved antimalarial drug that has been repurposed for cancer therapy because of its preferential antiproliferative effects on cancer versus normal cells. Mitochondria represent an attractive target for cancer therapy based on their regulatory role in proliferation and cell death. This study investigates whether DHA conjugated to innately fluorescent N-alkyl triphenylvinylpyridinium (TPVP) perturbs mitochondrial functions resulting in a differential toxicity of cancer versus normal cells. TPVP-DHA treatments resulted in a dose-dependent toxicity of human melanoma and pancreatic cancer cells, whereas normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments resulted in a G(1)-delay of the cancer cell cycle, which was also associated with a significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways. TPVP-DHA treatments perturbed mitochondrial functions, which correlated with increases in mitochondrial fission. In summary, TPVP mediated mitochondrial targeting of DHA enhanced cancer cell toxicity by perturbing mitochondrial functions and morphology.

Automated summary

The study showed that TPVP-DHA treatments resulted in dose-dependent toxicity of human melanoma and pancreatic cancer cells, while normal human fibroblasts were resistant to this treatment. TPVP-DHA treatments led to a G(1) delay in the cancer cell cycle, along with significant inhibition of the mTOR-metabolic and ERK1/2-proliferative signaling pathways.