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1.
Int J Cancer ; 152(5): 962-976, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36214789

RESUMO

Cervical cancer remains a major threat to women's health, especially in countries with limited medical resources, and new drugs are needed to improve patient survival and minimize adverse effects. Here, we examine the effects of a triphenylphosphonium (TPP)-conjugated pyrrole-imidazole polyamide (CCC-h1005) targeting the common homoplasmic mitochondrial DNA (mtDNA) cancer risk variant (ATP6 8860A>G) on the survival of cervical cancer cell lines, cisplatin-resistant HeLa cells and patient-derived cervical clear cell carcinoma cells as models of cervical cancer treatment. We found that CCC-h1005 induced death in these cells and suppressed the growth of xenografted HeLa tumors with no severe adverse effects. These results suggest that PIP-TPP designed to target mtDNA cancer risk variants can be used to treat many cervical cancers harboring high copies of the target variant, providing a foundation for clinical trials of this class of molecules for treating cervical cancer and other types of cancers.


Assuntos
Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Nylons/farmacologia , DNA Mitocondrial/genética , Células HeLa , Pirróis/farmacologia , Imidazóis/farmacologia
2.
Cancer Sci ; 113(4): 1321-1337, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35112436

RESUMO

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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Humanos , Imidazóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Nylons/farmacologia , Pirróis/farmacologia , Pirróis/uso terapêutico , Senoterapia
3.
Cancer Sci ; 112(6): 2504-2512, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33811417

RESUMO

Mitochondrial DNA (mtDNA) mutations occur frequently in cancer cells, and some of them are often homoplasmic. Targeting such mtDNA mutations could be a new method for killing cancer cells with minimal impact on normal cells. Pyrrole-imidazole polyamides (PIPs) are cell-permeable minor groove binders that show sequence-specific binding to double-stranded DNA and inhibit the transcription of target genes. PIP conjugated with the lipophilic triphenylphosphonium (TPP) cation can be delivered to mitochondria without uptake into the nucleus. Here, we investigated the feasibility of the use of PIP-TPP to target a mtDNA mutation in order to kill cancer cells that harbor the mutation. We synthesized hairpin-type PIP-TPP targeting the A3243G mutation and examined its effects on the survival of HeLa cybrid cells with or without the mutation (HeLamtA3243G cells or HeLamtHeLa cells, respectively). A surface plasmon resonance assay demonstrated that PIP-TPP showed approximately 60-fold higher binding affinity for the mutant G-containing synthetic double-stranded DNA than for the wild-type A-containing DNA. When added to cells, it localized in mitochondria and induced mitochondrial reactive oxygen species production, extensive mitophagy, and apoptosis in HeLamtA3243G cells, while only slightly exerting these effects in HeLamtHeLa cells. These results suggest that PIP-TPPs targeting mtDNA mutations could be potential chemotherapeutic drugs to treat cancers without severe adverse effects.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , Imidazóis/farmacologia , Mitocôndrias/genética , Neoplasias/genética , Pirróis/química , Compostos de Sulfônio/química , Sobrevivência Celular/efeitos dos fármacos , DNA Mitocondrial/genética , Células HeLa , Humanos , Imidazóis/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Nylons/química , Espécies Reativas de Oxigênio/metabolismo , Ressonância de Plasmônio de Superfície
4.
Biochem Biophys Res Commun ; 576: 93-99, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34482029

RESUMO

Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while preserving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs.


Assuntos
Antineoplásicos/farmacologia , DNA Mitocondrial/efeitos dos fármacos , Imidazóis/química , Mutação , Nylons/química , Compostos Organosselênicos/química , Pirróis/química , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/química , Apoptose/fisiologia , DNA Mitocondrial/genética , Feminino , Células HeLa , Humanos , Mitofagia/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
5.
Dalton Trans ; 46(9): 2760-2764, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28181609

RESUMO

Upon mixing acetylacetonedioxime and copper(ii) nitrate in water, the acetylacetonedioxime is spontaneously nitrosated at the central α-carbon and four of the nitrosated ligand molecules and five Cu ions self-assemble into a pentanuclear metallacrown complex, whose structure has been revealed by single crystal X-ray analysis and magnetic interactions between the Cu ions in the complex have been probed. The lability of the core Cu ion in the complex is suggested.

6.
Nanoscale ; 8(34): 15467-72, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27420651

RESUMO

We demonstrate up to ∼630-fold enhancement of the photocurrent from a porphyrin monolayer on a plasmonic Ag-array electrode showing plasmon absorption in the Q-band region relative to that on a planar Ag electrode. The photocurrent obtained by the Q-band excitation in the plasmonic electrodes even exceeded that obtained by the Soret-band excitation in a normal, nonplasmonic electrode.

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