RESUMO
Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N4 -arylsubstituted TSCs (N4 -TSCs) on human breast cancer cell lines. Studies on the effect of N4 -TSCs (T1, T2, and T3) were carried on MCF-7, MDA-MB 231, and BT 474 cell lines which differ in their expression of ER, PR, and Her2/neu. Non-transformed MCF-10A breast cell line were used as normal cells. Action of N4 -TSCs were evaluated by proliferation assay, quantification of apoptosis and cell cycle analysis. Modulation of clonogenic efficiency and migratory capacity by N4 -TSCs were also evaluated. We further investigated the effects of N4 -TSCs on ROS level and Ribonucleotide Reductase (RR) activity. We analyzed the action of these compounds on cellular mammosphere-forming capacity. We found that T1 and T2 had specific anti-tumor effect on all breast cancer cell lines based on their pro-apoptotic action and inhibitory effect on clonogenic efficiency and cell migration capacity. We also showed that both compounds increased ROS level and inhibited RR activity. Finally, we found that all N4 -TSCs diminished mammospehere-forming capacity of MCF-7 and BT 474 cells. N4 -TSCs showed specific anti-tumor action on human breast cancer cells independently their biomarkers expression pattern. Our results place these compounds as promising novel anti-tumor drugs with potential therapeutic application against different types of breast cancer.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Indanos/farmacologia , Tiossemicarbazonas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Indanos/síntese química , Células MCF-7 , Necrose , Espécies Reativas de Oxigênio/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores , Ribonucleotídeo Redutases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiossemicarbazonas/síntese químicaRESUMO
Aminoflavone (AFP 464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP 464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor size, and growth rate in the estrogen dependent, Tamoxifen-sensitive spontaneous M05 mouse model. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, we investigated whether AFP 464 modulates the immune response in our mouse model. Studies on the effect of AFP 464 on the immune system were carried in BALB/c mice bearing M05 semi-differentiated mammary adenocarcinomas that express estrogen and progesterone receptors. Splenic cells and tumor inflammatory infiltrates were studied by cytometric analyses. The modulation of splenocytes cytotoxic activity by AFP 464 was also evaluated. We further investigated the effects of AFP 464 on peritoneal macrophages by evaluating metalloproteinase, arginase, and iNOS activities. We found that AFP 464 increased splenic cytotoxic activity, diminished the number of systemic and local Treg lymphocytes, and MDSCs, and induced a M1 phenotype in peritoneal macrophages of M05 tumor bearing mice. Therefore, we conclude that AFP 464 modulates immune response which collaborates with its anti-tumor activity. Our results place the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens. J. Cell. Biochem. 118: 2841-2849, 2017. © 2017 Wiley Periodicals, Inc.