Dataset Information

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib.

ABSTRACT: Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy. We have previously identified a strongly synergistic drug combination (SDC), consisting of axitinib, erlotinib, and dasatinib that is active in renal cell carcinoma cells. In this study, we investigated the activity of this SDC in different CRC cell lines (SW620, HT29, and DLD-1) in more detail. SDC treatment significantly and synergistically decreased cell metabolic activity and induced apoptosis. The translation of the in-vitro-based results to in vivo conditions revealed significant CRC tumor growth inhibition, as evaluated in the chicken chorioallantoic membrane (CAM) model. Phosphoproteomics analysis of the tested cell lines revealed expression profiles that explained the observed activity. In conclusion, we demonstrate promising activity of an optimized mixture of axitinib, erlotinib, and dasatinib in CRC cells, and suggest further translational development of this drug mixture.

SUBMITTER: Berndsen RH

PROVIDER: S-EPMC6966484 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib.

Berndsen Robert H RH Swier Nathalie N van Beijnum Judy R JR Nowak-Sliwinska Patrycja P

Cancers 20191127 12

Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy. We have previously identified a strongly synergistic ...[more]

PMID: 31783534

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Project description:BackgroundTumors are heterogeneous in nature, composed of different cell populations with various mutations and/or phenotypes. Using a single drug to encounter cancer progression is generally ineffective. To improve the treatment outcome, multiple drugs of distinctive mechanisms but complementary anticancer activities (combination therapy) are often used to enhance antitumor efficacy and minimize the risk of acquiring drug resistance. We report here the synergistic effects of salinomycin (a polyether antibiotic) and dasatinib (a Src kinase inhibitor).MethodsFunctionally, both drugs induce cell cycle arrest, intracellular reactive oxygen species (iROS) production, and apoptosis. We rationalized that an overlapping of the drug activities should offer an enhanced anticancer effect, either through vertical inhibition of the Src-STAT3 axis or horizontal suppression of multiple pathways. We determined the toxicity induced by the drug combination and studied the kinetics of iROS production by fluorescence imaging and flow cytometry. Using genomic and proteomic techniques, including RNA-sequencing (RNA-seq), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western Blot, we subsequently identified the responsible pathways that contributed to the synergistic effects of the drug combination.ResultsCompared to either drug alone, the drug combination showed enhanced potency against MDA-MB-468, MDA-MB-231, and MCF-7 human breast cancer (BC) cell lines and tumor spheroids. The drug combination induces both iROS generation and apoptosis in a time-dependent manner, following a 2-step kinetic profile. RNA-seq data revealed that the drug combination exhibited synergism through horizontal suppression of multiple pathways, possibly through a promotion of cell cycle arrest at the G1/S phase via the estrogen-mediated S-phase entry pathway, and partially via the BRCA1 and DNA damage response pathway.ConclusionTranscriptomic analyses revealed for the first time, that the estrogen-mediated S-phase entry pathway partially contributed to the synergistic effect of the drug combination. More importantly, our studies led to the discoveries of new potential therapeutic targets, such as E2F2, as well as a novel drug-induced targeting of estrogen receptor β (ESR2) approach for triple-negative breast cancer treatment, currently lacking of targeted therapies.

Project description:Purpose:The use of a single-drug to encounter cancer progression is generally ineffective due to the tumors heterogeneity. To improve the clinical outcome, multiple drugs of distinctive mechanisms but complementary anticancer activities (combination therapy) are often used to enhance antitumor efficacy and minimize the risk of acquiring drug resistance. In this study, we proposed to use a combination of salinomycin (which targets anticancer stem cells) and dasatinib (an Src kinase inhibitor) for the treatment of breast cancer. The use of a RNA-seq is a combinatorial technique that allows to quantify global gene expression in biological samples. We employed this next generation sequencing technique to provide an initial insight into how Sal and Das alone, as well as in combination, modulated gene expression in the MDA-MB-468 human triple negative breast cancer cell line. Method: mRNA profiles of MDA-MB-468 cells treated with PBS (control), salinomycin, dasatinib, or the drug combination Sal + Das were generated by deep sequencing, in quadruplicate, using HiSeq4000 sequencer with single-end 50 bps reads. The results were validated by RT-qPCR analysis using StepOnePlus Real-timePCR system and SYBR Green assays. Results: RNA-seq data revealed that both salinomycin and dasatinib inhibit the expression of many downstream targeted genes of the STAT3, Wnt/beta-catenin, and hedgehog cell signaling pathways. The drug combination exhibited synergism through suppression of multiple pathways, leading to a promotion of cell cycle arrest at the G1/S phase mainly via the estrogen-mediated S-phase entry pathway, and partially via the BRCA1 and DNA damage response pathway. We also identified new salinomycin mechanisms involved in upregulating transcription factor 2. The study further led to a discovery of a new drug-induced targeting of estrogen receptor beta approach for triple-negative breast cancer treatment. Conclusion: Using RNA-seq, we identified for the first time the responsible pathways, including the estrogen-mediated S-phase entry pathway, that contributed to the synergistic effects of the drug combination Sal + Das. The discoveries of potential therapeutic targets, such as E2F2 as well as a novel drug-induced targeting of estrogen receptor beta (ESR2) approach were also described herein.We believe that using next generation approach to study drug mechanisms will allow us to identify more specific disease-relevant biomarkers for precision treatment of breast cancer, as well as other cancers in the future.

Dataset Information

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib.

Publications

Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib.

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