RESUMEN
There are innumerable anticancer compounds derived from either natural or synthetic origins. Many of these compounds have been further developed through structural modifications to not only inhibit cancer cell growth but also to exert an antimetastatic effect. This is achieved by attaching different substituents to generate different structure-activity relationships. This review highlights the effectiveness of different functional groups known to have antimigration and antiproliferation activities, such as fluoro, methoxy, methyl, amino, hydroxy, nitro, bromo, chloro, methylamino, ethoxy, carbonyl, iodo, and trifluoromethyl groups. Additionally, the positioning of these functional groups plays an important role in their anticancer activities, which was evident in one of our studies comparing analogues of a natural compound. Thus, this review suggests future recommendations for the design and development of improved anticancer drugs with higher efficacy.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Metástasis de la Neoplasia/patología , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects. MATERIALS AND METHODS: In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression. RESULTS: All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation. CONCLUSION: Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.
Asunto(s)
Antibacterianos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Alcoholes Bencílicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Mycobacterium/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Antibacterianos/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Alcoholes Bencílicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cisplatino/química , Difusión , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , FN-kappa B/metabolismo , Relación Estructura-ActividadRESUMEN
Nine analogs of 1'S-1'-acetoxychavicol acetate (ACA) were hemi-synthesized and evaluated for their anticancer activities against seven human cancer cell lines. The aim of this study was to investigate the anti-proliferative, apoptotic, and anti-migration effects of these compounds and to explore the plausible underlying mechanisms of action. We found that ACA and all nine analogs were non toxic to human mammary epithelial cells (HMECs) used as normal control cells, and only ACA, 1'-acetoxyeugenol acetate (AEA), and 1'-acetoxy-3,5-dimethoxychavicol acetate (AMCA) inhibited the growth of MDA-MB-231 breast cancer cells with a half-maximal inhibitory concentration (IC50) value of <30.0 µM based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay results, and were selected for further investigation. DNA fragmentation assays showed that these three compounds markedly induced apoptosis of MDA-MB-231 cells. Western blot analysis revealed increased expression levels of cleaved PARP, p53, and Bax, while decreased expression levels of Bcl-2 and Bcl-xL were seen after treatment, indicating that apoptosis was induced via the mitochondrial pathway. Moreover, ACA, AEA, and AMCA effectively inhibited the migration of MDA-MB-231 cells. They also downregulated the expression levels of pFAK/FAK and pAkt/Akt via the integrin ß1-mediated signaling pathway. Collectively, ACA and its hemi-synthetic analogs, AEA and AMCA are seen as potential anticancer agents following their abilities to suppress growth, induce apoptosis, and inhibit migration of breast cancer cells.