RRC ID 74901
著者 Tsuji K, Kida Y, Koshikawa N, Yamamoto S, Shinozaki Y, Watanabe T, Lin J, Nagase H, Takenaga K.
タイトル Suppression of non-small-cell lung cancer A549 tumor growth by an mtDNA mutation-targeting pyrrole-imidazole polyamide-triphenylphosphonium and a senolytic drug.
ジャーナル Cancer Sci
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.
巻・号 113(4)
ページ 1321-1337
公開日 2022-4-1
DOI 10.1111/cas.15290
PMID 35112436
PMC PMC8990788
MeSH 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
IF 4.966
リソース情報
ヒト・動物細胞 PC-14(RCB0446)