RESUMO
Although conventional therapeutic approaches have brought remarkable advantages for the treatment of breast cancer (BC), drug-resistance still remains as a leading cause of tumor recurrence in this malignancy. In the present study, we designed experiments to evaluate the therapeutic value of PI3K inhibition in combination with Arsenic trioxide (ATO) in MCF-7 cells. The results of our study manifested that BKM120 sensitized MCF-7 cells to the lower concentrations of ATO. The significant anti-cancer effect of PI3K inhibition became even more evident when we found that BKM120, either as a single agent or in combination with ATO, reduced clonogenic ability of anoikis-resistant stem-like MCF-7 cells. Our findings also showed that BKM120 augmented ATO-induced anti-proliferative effects through inducing G1 arrest and reducing the incorporation of BrdU into the synthesized DNA of drugs-treated cells, which was coupled with c-Myc-mediated suppression of hTERT expression. Moreover, we found that in the presence of PI3K inhibitor, ATO is able to more profoundly induce apoptosis in MCF-7 cells, as revealed by the increment in the percentage of haplodiploid sub-G1 cells and the externalization of phosphatidylserine. Real-time PCR analysis also revealed that probably down-regulation of survivin coupled with up-regulation of forkhead family transcription factors is responsible for the enhancive effect of drugs in this cell line. Conclusively, this study shed lights on the effect of PI3K inhibition in chemo-sensitivity of MCF-7 cells, disclosing that combination of BKM120 and ATO could be a promising therapeutic approach in BC.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/genética , Anoikis/efeitos dos fármacos , Anoikis/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fatores de Transcrição Forkhead/agonistas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilserinas/metabolismo , Transdução de Sinais , Survivina/antagonistas & inibidores , Survivina/genética , Survivina/metabolismo , Telomerase/antagonistas & inibidores , Telomerase/genética , Telomerase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
One of the most important species of the Bartonella genus is B. henselae that causes a zoonotic infection, cat scratch disease (CSD). The main source of the bacteria is cat and the carrier is Ctenocephalides felis flea. One hundred and forty nail and saliva samples were collected from 70 domestic cats. Positive samples for B. henselae were characterized by polymerase chain reaction (PCR) and sequencing. Sequences of gltA gene were trimmed using BioEdit software and then compared with the sequences of the same gene from B. henselae isolated from cats and humans in GenBank database. Phylogenic tree was constructed using CLC Sequence Viewer software and unweighted pair group method with arithmetic mean (UPGMA) method. Molecular assessments showed that five samples out of 70 nail samples (7.14%) and one sample out of 70 saliva samples (1.42%) were genetically positive for B. henselae. At least an 87.00% similarity was seen between the gene sequences from the current study and the reference sequences from the GenBank database. Phylogenic analysis has shown that strains isolated in this study were grouped in a different haplo group, compared to other strains. Among the Asian countries, the prevalence of the bacteria in Iran was close to that in Japan and Turkey. In conclusion, findings of this study showed the prevalence of B. henselae in Iranian cats which is important due to its public health issues, especially for the immunocompromised pet owners.
