Asciminib mitigates DNA damage stress signalling induced by cyclophosphamide in the ovary

AbstractCancer treatments often have adverse effects on the quality of life for young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signalling pathways activated by cyclophosphamide in mouse ovaries. Besides, we provide evidence that Asciminib did not interfere with the cytotoxic effect of cyclophosphamide in MCF7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without preventing the anticancer potential of cyclophosphamide. Altogether these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effect of cancer therapies.

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Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

International Journal of Molecular Sciences ◽

10.3390/ijms22031395 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1395

Author(s):

Luca Mattiello ◽

Giulia Pucci ◽

Francesco Marchetti ◽

Marc Diederich ◽

Stefania Gonfloni

Keyword(s):

Ovarian Reserve ◽

Kinase Inhibitor ◽

Concomitant Administration ◽

Cancer Therapies ◽

Cancer Treatments ◽

Abl Tyrosine Kinase ◽

Negative Impacts ◽

Abl Tyrosine Kinase Inhibitor

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

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Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

Cell Death and Disease ◽

10.1038/s41419-019-1961-y ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 3

Author(s):

Giovanna Bellusci ◽

Luca Mattiello ◽

Valentina Iannizzotto ◽

Sarah Ciccone ◽

Emiliano Maiani ◽

...

Keyword(s):

Ovarian Reserve ◽

Protein Kinase B ◽

Concomitant Administration ◽

In Vivo Studies ◽

Cancer Therapies ◽

Chemotherapeutic Drugs ◽

Forkhead Box ◽

Protective Strategy ◽

Sequential Mechanism

Abstract Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

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Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects

Drug Metabolism and Personalized Therapy ◽

10.1515/dmdi-2014-0026 ◽

2015 ◽

Vol 30 (1) ◽

Cited By ~ 8

Author(s):

Richat Abbas ◽

Joseph Boni ◽

Daryl Sonnichsen

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Concomitant Administration ◽

Abl Tyrosine Kinase ◽

Orally Bioavailable ◽

Abl Tyrosine Kinase Inhibitor ◽

Oral Doses

AbstractBosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men.Subjects received single oral doses of bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8–17); serial blood samples were analyzed.Bosutinib exposures were reduced following concomitant administration of rifampin vs. bosutinib alone, measured by peak plasma concentration (CConcomitant use of potent or moderate CYP3A inducers with bosutinib should be avoided because of the effects of drug-drug interaction observed between bosutinib and rifampin.

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Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

10.1101/526103 ◽

2019 ◽

Author(s):

Giovanna Bellusci ◽

Valentina Iannizzotto ◽

Sarah Ciccone ◽

Luca Mattiello ◽

Emiliano Maiani ◽

...

Keyword(s):

Ovarian Reserve ◽

Protein Kinase B ◽

Concomitant Administration ◽

In Vivo Studies ◽

Cancer Therapies ◽

Chemotherapeutic Drugs ◽

Forkhead Box ◽

Protective Strategy ◽

Sequential Mechanism

Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

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Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽

10.1182/blood.v96.9.3195 ◽

2000 ◽

Vol 96 (9) ◽

pp. 3195-3199 ◽

Cited By ~ 215

Author(s):

J. Tyler Thiesing ◽

Sayuri Ohno-Jones ◽

Kathryn S. Kolibaba ◽

Brian J. Druker

Keyword(s):

Clinical Trials ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Single Agent ◽

Myelogenous Leukemia ◽

Hematopoietic Stem ◽

Abl Tyrosine Kinase ◽

Abl Tyrosine Kinase Inhibitor

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

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