Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes

Xue, Tao; Luo, Peihua; Zhu, Hong; Zhao, Yu-Qin; Wu, Honghai; Gai, Renhua; Wu, Yi; Yang, Bo; Yang, Xiaochun; He, Qiaojun

doi:10.1016/j.taap.2012.04.010

Cited by 65 publications

(60 citation statements)

References 37 publications

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“…Double staining on rat lungs with the endothelial marker vWF and 8-oxo-2′-deoxyguanosine (8-oxo-dG), a marker of DNA oxidation, revealed that in vivo dasatinib treatment led to an increased expression of 8-oxo-dG in pulmonary ECs in comparison with vehicle-and imatinib-treated rats ( Figure 5A). Consistently with a previous study (27), we also found significant increased levels of oxidized proteins (protein carbonyl products) and glutathione in lung homogenates from rats treated with dasatinib compared with vehicle or imatinib ( Figure 5B), in a dose-dependent manner. Moreover, intracellular ROS were also measured by 2 different detection methods, namely fluorogenic probes (CellRox) and dihydroethidium, in cultured human pulmonary ECs, confirming a dose-dependent dasatinib-induced increase in endothelial ROS ( Figure 5C).…”

Section: Resultssupporting

confidence: 92%

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

Guignabert¹,

Phan²,

Seferian³

et al. 2016

Journal of Clinical Investigation

204

186

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Section: Resultssupporting

confidence: 92%

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

Guignabert¹,

Phan²,

Seferian³

et al. 2016

Journal of Clinical Investigation

204

186

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“…26) Several studies have provided evidence that dasatinib and gefitinib exhibit antitumor activity by ROS generation and apoptosis induction. 27,28) Our results demonstrated that the incubation of MCF-7 cells with cladribine, gefitinib or dasatinib alone or in combination, increased ROS generation, decreased ΔΨ m , down-regulated expression of the anti-apoptosis protein Bcl-2, and induced mitochondriamediated apoptosis. In conclusion, the findings presented in this study demonstrated, for the first time, that cladribine and gefitinib, and cladribine and dasatinib synergistically inhibited the growth of MCF-7 cells in vitro.…”

Section: Discussionmentioning

confidence: 65%

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Zhang

Yuan

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Antimetabolite drugs, including the adenosine deaminase inhibitor cladribine, have been shown to induce apoptosis in a variety of cancer cells, and have been widely used in clinical trials of various cancers in conjunction with tyrosine kinase inhibitors (TKIs). Combination treatment with cladribine and gefitinib or dasatinib is expected to have a synergistic inhibitory effect on breast cancer cell growth. Our results demonstrated that the combination treatment had synergistic activity against human breast cancer (MCF-7) cells, enhanced G 2 /M cell arrest and reactive oxygen species (ROS) generation, and increased the loss of mitochondrial membrane potential and cell apoptosis. In addition, the combination treatment decreased Bcl-2 expression. Our results demonstrated that cladribine in combination with gefitinib or dasatinib exerted synergistic anticancer effects on MCF-7 cells by inducing cell cycle arrest, ROS production and apoptosis through the mitochondria-mediated intrinsic pathway.Key words cladribine; gefitinib; dasatinib; breast cancer; combination therapy Breast cancer is the most common malignant tumor and the leading cause of cancer-related deaths in women.1,2) Current treatment for breast cancer includes surgery, radiotherapy and drug therapy, with drug therapy including hormone therapy, chemotherapy and immunotherapy.3,4) The pathogenesis of breast cancer has been studied in-depth, 5) and many drugs have emerged for the treatment of breast cancer, with chemotherapy remaining the mainstay of treatment for breast cancer in addition to surgery. In the clinic, the main chemotherapeutic agents used to treat breast cancer include cisplatin and paclitaxel, docetaxel, curcumin, navelbine, and oxaliplatin. Although these chemotherapy drugs are widely used in the treatment of breast cancer, they often have severe side effects. 6)Recent studies have found that multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK), are involved in breast cancer cell proliferation, and targets of these pathways, such as epidermal growth factor receptor (EGFR), Akt, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF-1R), human epidermal growth factor receptor-2 (HER2), have become anti-breast cancer drug targets. 7,8) We are known to target anti-breast cancer drugs trastuzumab, lapatinib and so on, but the development of drug resistance in patients has limited their clinical use. With the integration of various disciplines of drug research, the role of multiple targets in biological signaling networks and pathways to achieve appropriate physiological and pathological outcomes has been well studied.9) A growing body of literature has also shown that drug combinations have synergistic anti-cancer effects through the inhibition of these targets. [10][11][12][13][14] In the clinic, combination chemotherapy for breast cancer is widely used, including drugs such as dasatinib and adriamycin, and has shown excellent results. 15)The clinical app...

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Section: Downstream Toxicity Mechanisms Of Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…Xue et al, examined dasatinib-induced hepatic injury in rat primary hepatocytes and in vivo in rats treated with dasatinib [58]. Dasatinib induced hepatic injury in vitro in a time- and dose-dependent manner in rat primary hepatocytes [58]. Treatment of rats with dasatinib (25 mg/kg/day) for 10 days increased liver injury markers, including elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH).…”

Section: Downstream Toxicity Mechanisms Of Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

Jackson

Durandis

2018

IJMS

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Tyrosine kinase inhibitors are a rapidly expanding class of molecular targeted therapies for the treatment of various types of cancer and other diseases. An increasing number of clinically important small molecule tyrosine kinase inhibitors have been shown to undergo cytochrome P450-mediated bioactivation to form chemically reactive, potentially toxic products. Metabolic activation of tyrosine kinase inhibitors is proposed to contribute to the development of serious adverse reactions, including idiosyncratic hepatotoxicity. This article will review recent findings and ongoing studies to elucidate the link between drug metabolism and tyrosine kinase inhibitor-associated hepatotoxicity.

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Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes

Cited by 65 publications

References 37 publications

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

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