ArticleThe Journal of biological chemistry2013
Pan-mammalian target of rapamycin (mTOR) inhibitor AZD8055 primes rhabdomyosarcoma cells for ABT-737-induced apoptosis by down-regulating Mcl-1 protein.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 63 citations in OpenAlex.
- Molecular Targets in Alveolar Rhabdomyosarcoma: A Narrative Review of Progress and Pitfalls.International journal of molecular sciences · 2025Review
- The Emerging Role and Clinical Significance of PI3K-Akt-mTOR in Rhabdomyosarcoma.Biomolecules · 2025Review
- Unlocking the power of probiotics, postbiotics: targeting apoptosis for the treatment and prevention of digestive diseases.Frontiers in nutrition · 2025Review
- Disrupting resistance: novel therapeutic approaches to combat multidrug resistance in fusion-negative rhabdomyosarcoma.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Dihydroartemisinin Enhances the Therapeutic Efficacy of BH3 Mimetic Inhibitor in Acute Lymphoblastic Leukemia Cells via Inhibition of Mcl-1.Asian Pacific journal of cancer prevention : APJCP · 2024Article
- Enhancement of the Sensitivity of the Acute Lymphoblastic Leukemia Cells to ABT-737 by Formononetin.International journal of molecular and cellular medicine · 2024Article
- The Cytotoxic Effect of Curcumin in Rhabdomyosarcoma Is Associated with the Modulation of AMPK, AKT/mTOR, STAT, and p53 Signaling.Nutrients · 2023Article
- Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex.iScience · 2022Article
- mTORC1 stimulates cell growth through SAM synthesis and mMolecular cell · 2021Article
- Molecular Targets for Novel Therapeutics in Pediatric Fusion-Positive Non-CNS Solid Tumors.Frontiers in pharmacology · 2021Review
- Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance.Cell death & disease · 2020Article
- HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.The Journal of clinical investigation · 2020Article
- Targeting apoptosis in cancer therapy.Nature reviews. Clinical oncology · 2020Review
- miRNA Modulation and Antitumor Activity by the Extra-Virgin Olive Oil Polyphenol Oleacein in Human Melanoma Cells.Frontiers in pharmacology · 2020Article
- Destined to Die: Apoptosis and Pediatric Cancers.Cancers · 2019Review
- Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition.EMBO molecular medicine · 2019Article
- Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.Oncotarget · 2019Article
- Genetics, epigenetics and redox homeostasis in rhabdomyosarcoma: Emerging targets and therapeutics.Redox biology · 2019Review
- Current and Future Treatment Strategies for Rhabdomyosarcoma.Frontiers in oncology · 2019Review
- ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer.Science advances · 2018Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The PI3K/mammalian Target of Rapamycin (mTOR) pathway is often aberrantly activated in rhabdomyosarcoma (RMS) and represents a promising therapeutic target. Recent evaluation of AZD8055, an ATP-competitive mTOR inhibitor, by the Preclinical Pediatric Testing Program showed in vivo antitumor activity against childhood solid tumors, including RMS. Therefore, in the present study, we searched for AZD8055-based combination therapies. Here, we identify a new synergistic lethality of AZD8055 together with ABT-737, a BH3 mimetic that antagonizes Bcl-2, Bcl-xL, and Bcl-w but not Mcl-1. AZD8055 and ABT-737 cooperate to induce apoptosis in alveolar and embryonal RMS cells in a highly synergistic fashion (combination index < 0.2). Synergistic induction of apoptosis by AZD8055 and ABT-737 is confirmed on the molecular level, as AZD8055 and ABT-737 cooperate to trigger loss of mitochondrial membrane potential, activation of caspases, and caspase-dependent apoptosis that is blocked by the pan-caspase inhibitor Z-VAD-fmk. Similar to AZD8055, the PI3K/mTOR inhibitor NVP-BEZ235, the PI3K inhibitor NVP-BKM120 and Akt inhibitor synergize with ABT-737 to trigger apoptosis, whereas no cooperativity is found for the mTOR complex 1 inhibitor RAD001. Interestingly, molecular studies reveal a correlation between the ability of different PI3K/mTOR inhibitors to potentiate ABT-737-induced apoptosis and to suppress Mcl-1 protein levels. Importantly, knockdown of Mcl-1 increases ABT-737-induced apoptosis similar to AZD8055/ABT-737 cotreatment. This indicates that AZD8055-mediated suppression of Mcl-1 protein plays an important role in the synergistic drug interaction. By identifying a novel synergistic interaction of AZD8055 and ABT-737, our findings have important implications for the development of molecular targeted therapies for RMS.
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