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We are analyzing https://www.nature.com/articles/s41419-017-0170-9.

Title:
Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death | Cell Death & Disease
Description:
Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
Website Age:
30 years and 10 months (reg. 1994-08-11).

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  • Science
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Custom-built

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๐ŸŒ  Phenomenal Traffic: 5M - 10M visitors per month


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Direct Advertisers (10)
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Display Ads {๐ŸŽฏ}

$63,100 per month
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Keywords {๐Ÿ”}

cell, cells, cancer, pubmed, tak, autophagy, article, google, scholar, combination, treatment, cas, fig, death, inhibitor, takac, viability, central, activation, treated, lines, flt, assay, cma, breast, sum, aml, chaperonemediated, leukemia, nature, inhibitors, signaling, conditions, effect, kinase, shown, data, performed, induce, inhibition, degradation, therapy, inhibit, combined, negative, levels, pathways, proliferation, resistance, concentrations,

Topics {โœ’๏ธ}

nature portfolio privacy policy clinical research nature advertising bioactive libraries tnf-a-induced neutrophil apoptosis thermo fisher scientific r-7-cl-o-nec-1โ€“10โ€‰ฮผm transforming growth factor-beta reprints celltiter-gloยฎ luminescent assay japan epidermal-growth-factor receptors cell culture media override stromal-mediated chemoresistance hyperstar polymer-based nanoparticles cancer development triple-negative breast cancer acute myeloid leukemia small-cell lung cancer mitogen-activated protein kinase androgen-independent prostate cancer cancer-related flt3 mutations chemical library screening luminescence-based viability assay permissions small-cell lung cancers mda-7 enhances apoptosis-induction mimics glucose-free conditions high proliferative activity culture media activating phosphoinositol-3-kinase author correspondence original author ludwig cancerย center breast triple negative human clinical trials social media induce ligand-independent activation glucose-free conditions shows iii phosphoinositide 3-kinase strong combination index published maps chaperone-mediated autophagy activation promotes cell death mutant flt3-positive aml article ouchida junying yuan tak-165/ac220 combination induces

Questions {โ“}

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Schema {๐Ÿ—บ๏ธ}

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         description:Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
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      description:Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
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