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

Kemal Alpay, Mehdi Farshchian, Johanna Tuomela, Jouko Sandholm, Kaappo Aittokallio, Elina Siljamäki, Marko Kallio, Veli-Matti Kähäri, Sakari Hietanen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

4 Citations (Scopus)

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.
Original languageEnglish
Article numbere105526
JournalPLoS ONE
Volume9
Issue number8
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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Mitoxantrone
phosphotransferases (kinases)
Phosphotransferases
Cells
Chemotherapy
DNA damage
drug therapy
apoptosis
DNA Damage
small interfering RNA
Neoplasms
Apoptosis
HeLa Cells
Drug Therapy
Small Interfering RNA
cells
DNA
drugs
doxorubicin
Papillomaviridae

Cite this

Alpay, K., Farshchian, M., Tuomela, J., Sandholm, J., Aittokallio, K., Siljamäki, E., ... Hietanen, S. (2014). Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone. PLoS ONE, 9(8), [e105526]. https://doi.org/10.1371/journal.pone.0105526
Alpay, Kemal ; Farshchian, Mehdi ; Tuomela, Johanna ; Sandholm, Jouko ; Aittokallio, Kaappo ; Siljamäki, Elina ; Kallio, Marko ; Kähäri, Veli-Matti ; Hietanen, Sakari. / Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone. In: PLoS ONE. 2014 ; Vol. 9, No. 8.
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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.",
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Alpay, K, Farshchian, M, Tuomela, J, Sandholm, J, Aittokallio, K, Siljamäki, E, Kallio, M, Kähäri, V-M & Hietanen, S 2014, 'Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone', PLoS ONE, vol. 9, no. 8, e105526. https://doi.org/10.1371/journal.pone.0105526

Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone. / Alpay, Kemal; Farshchian, Mehdi; Tuomela, Johanna; Sandholm, Jouko; Aittokallio, Kaappo; Siljamäki, Elina; Kallio, Marko; Kähäri, Veli-Matti; Hietanen, Sakari (Corresponding Author).

In: PLoS ONE, Vol. 9, No. 8, e105526, 2014.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone

AU - Alpay, Kemal

AU - Farshchian, Mehdi

AU - Tuomela, Johanna

AU - Sandholm, Jouko

AU - Aittokallio, Kaappo

AU - Siljamäki, Elina

AU - Kallio, Marko

AU - Kähäri, Veli-Matti

AU - Hietanen, Sakari

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AB - 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.

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DO - 10.1371/journal.pone.0105526

M3 - Article

VL - 9

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 8

M1 - e105526

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Alpay K, Farshchian M, Tuomela J, Sandholm J, Aittokallio K, Siljamäki E et al. Inhibition of c-Abl kinase activity renders cancer cells highly sensitive to mitoxantrone. PLoS ONE. 2014;9(8). e105526. https://doi.org/10.1371/journal.pone.0105526