Suppression of non-small-cell lung cancer A549 tumor growth by an mtDNA mutation-targeting pyrrole-imidazole polyamide-triphenylphosphonium and a senolytic drug

Cancer Sci. 2022 Apr;113(4):1321-1337. doi: 10.1111/cas.15290. Epub 2022 Feb 16.

Abstract

Certain somatic mutations in mtDNA were associated with tumor progression and frequently found in a homoplasmic state. We recently reported that pyrrole-imidazole polyamide conjugated with the mitochondria-delivering moiety triphenylphosphonium (PIP-TPP) targeting an mtDNA mutation efficiently induced apoptosis in cancer cells with the mutation but not normal cells. Here, we synthesized the novel PIP-TPP, CCC-021-TPP, targeting ND6 14582A > G homoplasmic missense mutation that is suggested to enhance metastasis of non-small-cell lung cancer A549 cells. CCC-021-TPP did not induce apoptosis but caused cellular senescence in the cells, accompanied by a significant induction of antiapoptotic BCL-XL. Simultaneous treatment of A549 cells with CCC-021-TPP and the BCL-XL selective inhibitor A-1155463 resulted in apoptosis induction. Importantly, the combination induced apoptosis and suppressed tumor growth in an A549 xenografted model. These results highlight the potential of anticancer therapy with PIP-TPPs targeting mtDNA mutations to induce cell death even in apoptosis-resistant cancer cells when combined with senolytics.

Keywords: apoptosis; mitochondria; mtDNA; mutation; pyrrole-imidazole polyamide.

MeSH terms

  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Cell Line, Tumor
  • DNA, Mitochondrial / genetics
  • Humans
  • Imidazoles
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Mutation
  • Nylons / pharmacology
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use
  • Senotherapeutics

Substances

  • DNA, Mitochondrial
  • Imidazoles
  • Nylons
  • Pyrroles
  • Senotherapeutics
  • imidazole