RESUMO
The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC50 value of 1.9 ± 0.3 µM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/ß-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3ß) revealed that down-regulation of ß-catenin was promoted by GSK-3ß-induced phosphorylation of ß-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/ß-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/ß-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer.
RESUMO
Altered energy metabolism is an emerging hallmark of cancer and plays a pivotal in cell survival, proliferation, and biosynthesis. In a rapidly proliferating cancer, energy metabolism acts in synergism with epithelial-to-mesenchymal transition (EMT), enabling cancer stemness, dissemination, and metastasis. In this study, an interconnected functional network governing energy metabolism and EMT signaling pathways was targeted through the concurrent inhibition of IR, ITGB1, and CD36 activity. A novel multicomponent MD simulation approach was employed to portray the simultaneous inhibition of IR, ITGB1, and CD36 by a 2:1 combination of Pimozide and Ponatinib. Further, in-vitro studies revealed the synergistic anticancer efficacy of drugs against monolayer as well as tumor spheroids of breast cancer cell lines (MCF-7 and MDA-MB-231). In addition, the combination therapy exerted approximately 40% of the apoptotic population and more than 1.5- to 3-fold reduction in the expression of ITGB1, IR, p-IR, IRS-1, and p-AKT in MCF-7 and MDA-MB-231 cell lines. Moreover, the reduction in fatty acid uptake, lipid droplet accumulation, cancer stemness, and migration properties were also observed. Thus, targeting IR, ITGB1, and CD36 in the interconnected network with the combination of Pimozide and Ponatinib represents a promising therapeutic approach for breast cancer.
Assuntos
Neoplasias da Mama , Antígenos CD36 , Metabolismo Energético , Transição Epitelial-Mesenquimal , Integrina beta1 , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Integrina beta1/metabolismo , Antígenos CD36/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Metabolismo Energético/efeitos dos fármacos , Células MCF-7 , Imidazóis/farmacologia , Piridazinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Triple-negative breast cancer (TNBC) is characterized by the complex tumor microenvironment (TME) consisting of an abundance of mesenchymal stem cells (MSCs), which is known to facilitate epithelial-to-mesenchymal transition (EMT). The development of single-cell genomics is a powerful method for defining the intricate genetic landscapes of malignancies. In this study, we have employed single-cell RNA sequencing (scRNA-seq) to dissect the intra-tumoral heterogeneity and analyze the single-cell transcriptomic landscape to detect rare consequential cell subpopulations of significance. The scRNA-seq analysis of TNBC and Normal patient derived samples revealed that EMT markers and transcription factors were most upregulated in MSC population. Further, exploration of gene expression analysis among TNBC and Normal patient-derived MSCs ascertained the role of SQSTM1/P62 and Wnt/ß-catenin in TNBC progression. Wnt/ß-catenin and Wnt/PCP signaling pathways are prominent contributors of EMT, stemness, and cancer stem cell (CSC) properties of TNBC. SQSTM1/P62 cooperates with the components of the Wnt/PCP signaling pathway and is critically involved at the interface of autophagy and EMT. Moreover, siRNA targeting SQSTM1/P62 and inhibitor of Wnt/ß-catenin (FH535) in conjunction was used to explore molecular modification of EMT and stemness markers. Although SQSTM1/P62 is not crucial for cell survival, cytotoxicity assay revealed synergistic interaction between the siRNA/inhibitor. Modulation of these important pathways helped in reduction of expression of genes and proteins contributing to CSC properties. Gene and protein expression analysis revealed the induction of EMT to MET. Moreover, co-treatment resulted in inactivation of non-canonical Wnt VANGL2-JNK signaling axis. The synergistic impact of inhibition of SQSTM1/P62 and Wnt/ß-catenin signaling facilitates the development of a potential therapeutic regimen for TNBC.
Assuntos
Transição Epitelial-Mesenquimal , Células-Tronco Neoplásicas , Proteína Sequestossoma-1 , Análise de Célula Única , Neoplasias de Mama Triplo Negativas , Via de Sinalização Wnt , Feminino , Humanos , beta Catenina/metabolismo , beta Catenina/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Análise de Célula Única/métodos , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente Tumoral/genética , Via de Sinalização Wnt/genéticaRESUMO
Emerging evidence portray the involvement of epigenomic reprogramming in the onset and progression of several malignancies, including breast cancer. Histone acetyltransferase (HAT) p300 is a critical epigenetic regulator that acts as a transcription co-activator and regulates various cellular processes. p300 is overexpressed in breast cancer and promotes cellular invasion and survival, making it a promising druggable target. In this study, the relevance of p300 in different cancer pathways was established. Virtual screening of the FDA-approved drug library was carried out using molecular docking, and the top 10 potential repurposed drugs were identified. Further, recalculation of binding free energy of drug-p300 complexes was carried out using molecular mechanics Poisson-Boltzmann and surface area (MM-PBSA) method after molecular dynamic simulation. Based on molecular dynamic simulation parameters and binding free energy analysis, two drugs, namely Netarsudil (-305.068 kJ/mol) and Imatinib (-260.457 kJ/mol), were identified as potential repurposed drugs to inhibit the activity of p300. In conclusion, these findings suggest, Netarsudil and Imatinib might be a potential repurposed drug to combat breast cancer via p300 inhibition.Communicated by Ramaswamy H. Sarma.
RESUMO
The synthesis of hitherto unreported 3-sulfenylindole derivatives is achieved from 4-hydroxy-2H-chromene-2-thione (1) and indole (2) by employing an oxidative cross-dehydrogenative coupling reaction using a combination of 10 mol% of molecular iodine and 1 equivalent of TBHP in DMSO at room temperature. Then, the 3-sulfenylindole derivatives 3a, 3b, 3d, 3f, 3 h, and 3 k were converted into their corresponding sulfone derivatives because of lead likeness properties. Subsequently, a target prediction and docking study of six sulfone derivatives (5a-f) was performed, and four sulfones, namely 5a, 5d, 5e, and 5f, were selected for further in-vitro studies. The four sulfones mentioned above exhibited prominent anti-proliferative activity on breast cancer (MCF7) cell lines. In addition, this reaction was exergonic through quantum chemical analysis of the mechanistic steps. The salient features of this reaction are mild reaction conditions, good yields, and broad substrate scope.