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) |