Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Wu, Yu-Shan; Zhang, Dongxing; Yuan, Quan; Liu, Dongwu; Li, Yanyan; Zhang, Xiuzhen

doi:10.1248/cpb.c17-00261

Cited by 14 publications

(10 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cladribine activates the intrinsic pathway of apoptosis by inducing caspases such as caspase −3, 7, −8, or −9. A decrease in the mitochondrial membrane potential leads to changes in the intracellular levels of calcium 9,33 . The present study clearly showed that the new derivatives significantly increased the levels of calcium ions to a greater extent than CLA.…”

Section: Discussionmentioning

confidence: 99%

“…Another mechanism underlying the effect of cladribine is the induction of cell cycle arrest and condensation of chromosomes. Cladribine leads to the accumulation of cells in the G2/M phase at the expense of the G1 phase 9 . In HL-60 cells, the CLA-FMOR derivative increased the number of cells in the sub-G1 phase.…”

Section: Discussionmentioning

confidence: 99%

“…Cladribine also promotes arrest of the cell cycle in the G 2 /M phase, condensation of chromosomes and DNA fragmentation. Cladribine induces apoptosis by accumulation of double-stranded DNA breaks and by increasing the level of γH2AX 9,10 , . The first step of activating cladribine is catalyzed by deoxycytidine kinase (dCK).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antileukemic activity of novel adenosine derivatives

Poczta

Rogalska

Łukawska

et al. 2019

Sci Rep

View full text Add to dashboard Cite

The present study investigated the effect of cladribine (CLA) and six of its derivatives containing a formamidine group at position 6 (CLA-FDM, CLA-FPAZ, CLA-FPIR, CLA-FPIP, CLA-FHEX, and CLA-FMOR) on acute promyelocytic, lymphoblastic, and acute monocytic leukemia cells. The role of ATR kinase in deoxycytidine kinase (dCK) activation in response to DNA damage was assessed. The presence of DNA lesions was assessed by measurement phosphorylation of H2AX and by using the alkaline comet assay with proteinase K post-treatment following assessment of the cell cycle. Apoptotic events such as alterations in intracellular calcium concentration, caspase-3/7 activity and increased sub-G1 cell population were measured. CLA derivatives were highly effective against leukemic cells, showing high cytotoxicity, causing DNA fragmentation, and inducing DNA-protein cross-links in leukemic cells. CLA-FMOR showed the highest efficacy. CLA derivatives increased the levels of intracellular calcium ions, caspase-3/7 and the percentage of sub-G1 apoptotic cells and blocked cells in the S phase of the cell cycle to a greater extent than free CLA. The selective ATR inhibitor VE-821 significantly suppressed the increase in dCK activity and decreased basal dCK activity. The present results suggested that ATR kinase controls dCK activity in response to synthetic CLA derivatives.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antileukemic activity of novel adenosine derivatives

Poczta

Rogalska

Łukawska

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Sal has been shown to induce iROS production, suppress the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathways (PI3K/AKT/mTOR), and cause apoptosis in prostate, brain, and breast cancer cells [ 42 – 44 ]. Das can also induce iROS [ 45 ]. These provided the rationale for us to investigate whether the drug combination would enhance the ROS increase in different human BC cell lines including MDA-MB-468, MDA-MB-231, and MCF-7, and thereby promote cytotoxicity compared to using Sal or Das alone.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

et al. 2020

View full text Add to dashboard Cite

Background: Tumors 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). Methods: Functionally, 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 transcriptionquantitative polymerase chain reaction (RT-qPCR), and Western Blot, we subsequently identified the responsible pathways that contributed to the synergistic effects of the drug combination. Results: Compared 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.

show abstract

“…Additionally, the synergistic activities of dasatinib + vorinostat, cladribine+dasatinib and cladribine+gefitinib were analyzed in detail. The results of the analysis showed that these three combinatorial drugs exert synergistic anti-cancer effects on MCF-7 cells by inducing cell cycle arrest, reactive oxygen (ROS) production and apoptosis through mitochondrial-mediated endogenous pathways [ 41 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes

Yuan

Liu

et al. 2018

Molecules

Self Cite

View full text Add to dashboard Cite

Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most diseases are not caused by a single pathogenic factor, but by multiple disease genes, in particular, interacting disease genes. Thus, it is reasonable to consider that targeting epistatic disease genes may enhance the therapeutic effects of combinatorial drugs. In this study, synthetic lethality gene pairs of tumors, similar to epistatic disease genes, were first targeted by combinatorial drugs, resulting in the enrichment of the combinatorial drugs with cancer treatment, which verified our hypothesis. Then, conventional epistasis detection software was used to identify epistatic disease genes from the genome wide association studies (GWAS) dataset. Furthermore, combinatorial drugs were predicted by targeting these epistatic disease genes, and five combinations were proven to have synergistic anti-cancer effects on MCF-7 cells through cell cytotoxicity assay. Combined with the three-dimensional (3D) genome-based method, the epistatic disease genes were filtered and were more closely related to disease. By targeting the filtered gene pairs, the efficiency of combinatorial drug discovery has been further improved.

show abstract

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Cited by 14 publications

References 30 publications

Antileukemic activity of novel adenosine derivatives

Antileukemic activity of novel adenosine derivatives

Transcriptomic insight into salinomycin mechanisms in breast cancer cell lines: synergistic effects with dasatinib and induction of estrogen receptor β

Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes

Contact Info

Product

Resources

About