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Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

ABSTRACT: Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX) and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The difference in MX and doxorubicin was related to significant augmentation of DNA damage. Transcriptionally active p53 accumulated in cells in which human papillomavirus E6 normally degrades p53. The combination treatment resulted in caspase activation and apoptosis, but this effect did not depend on either p53 or p73 activity. Despite increased p53 activity, the cells arrested in G2 phase became defective in this checkpoint, allowing cell cycle progression. The effect after MX treatment depended partially on c-Abl: Short interfering RNA knockdown of c-Abl rendered HeLa cells less sensitive to MX. The effect of imatinib was decreased by c-Abl siRNA suggesting a role for catalytically inactive c-Abl in the death cascade. These findings indicate that MX has a unique cytotoxic effect when the kinase activity of c-Abl is inhibited. The treatment results in increased DNA damage and c-Abl-dependent apoptosis, which may offer new possibilities for potentiation of cancer chemotherapy.

SUBMITTER: Alpay K

PROVIDER: S-EPMC4141754 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

Alpay Kemal K Farshchian Mehdi M Tuomela Johanna J Sandholm Jouko J Aittokallio Kaappo K Siljamäki Elina E Kallio Marko M Kähäri Veli-Matti VM Hietanen Sakari S

PloS one 20140822 8

Although c-Abl has increasingly emerged as a key player in the DNA damage response, its role in this context is far from clear. We studied the effect of inhibition of c-Abl kinase activity by imatinib with chemotherapy drugs and found a striking difference in cell survival after combined mitoxantrone (MX) and imatinib treatment compared to a panel of other chemotherapy drugs. The combinatory treatment induced apoptosis in HeLa cells and other cancer cell lines but not in primary fibroblasts. The ...[more]

PMID: 25148385

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Project description:Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5 000 000 cases worldwide. Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded α-synuclein activates c-Abl, which phosphorylates α-synuclein and promotes α-synuclein pathology within the affected neurons. Additionally, c-Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post-mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated α-synuclein, consistent with the activation of c-Abl in human disease. Although the c-Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double-blind trials, novel c-Abl inhibitors have been developed that accumulate in the brain and may inhibit c-Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c-Abl in the neurodegenerative disease process and consider the translational potential of c-Abl inhibitors from model studies to disease-modifying therapies for Parkinson's disease. © 2021 Inhibikase Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

Publications

Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone.

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