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Lestaurtinib is Cytotoxic to Oxaliplatin-resistant Transitional Cell Carcinoma Cell Line T24 In Vitro

Pei-Chun Lai a, b, Te-Chao Fang c, d, Chuan-Chu Cheng e, Ted H. Chiu a, f,  Yen-Ta Huang a, d

aInstitute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan
bDepartment of Pediatrics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
cDepartment of Medicine, Tzu Chi University, Hualien, Taiwan
dDepartment of Nephrology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
eDepartment of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
fDepartment of Pharmacology, Tzu Chi University, Hualien, Taiwan
gDepartment of Surgical Critical Care Unit, Buddhist Tzu Chi General Hospital, Hualien, Taiwan

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Abstract

Objective
Patients with bladder cancer have responded poorly to oxaliplatin therapy in clinical trials. Blockade of receptor tyrosine kinases is considered a good strategy in cancer therapy. Our previous studies have demonstrated the crucial roles of brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B (TrkB) in transitional cell carcinoma (TCC). The aim of this study was to examine the cytotoxic effects of lestaurtinib, a new pan-Trk inhibitor, and oxaliplatin on bladder cancer cell lines.
Materials and Methods
BFTC905 and T24 TCC cell lines were used for investigation in vitro. The effects of oxaliplatin and/or lestaurtinib on cell viability, apoptosis, and expression of survivin and securin were assessed. MTT assay was used for cytotoxic evaluation. DNA fragments were detected in both the culture medium and cytoplasm to differentiate the types of cell death (apoptosis vs. necrosis). Western blots were used to analyze the expression of survivin and securin after oxaliplatin and/or lestaurtinib treatment.
Results
Oxaliplatin at 3 μg/mL elicited cytotoxicity on BFTC905 but not T24 cells 48 hours after treatment. The addition of 1 or 3 μM lestaurtinib to oxaliplatin did not exert additive cytotoxic effects on BFTC905 cells. Although oxaliplatin at 3 μg/mL had no effect on T24 cells, the addition of 1 or 3 μM lestaurtinib demonstrated concentration-dependent inhibitory effects. Apoptosis of T24 cells was observed after treatment with lestaurtinib alone and lestaurtinib plus oxaliplatin. Furthermore, in T24 cells, the expression of survivin was inhibited by a combination of lestaurtinib and oxaliplatin, while securin expression was inhibited by lestaurtinib alone and lestaurtinib with oxaliplatin.
Conclusion
Lestaurtinib may be a potential new drug for the targeted therapy of oxaliplatin-resistant TCC. Further in vivo studies are needed.


Keywords

Lestaurtinib; Oxaliplatin; Securin; Survivin; Transitional cell carcinoma


 

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