@article{APS7935,
author = {Qi Qi and Xia Liu and Shiyong Li and Harish C Joshi and Keqiang Ye},
title = {Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth},
journal = {Acta Pharmacologica Sinica},
volume = {34},
number = {7},
year = {2016},
keywords = {},
abstract = {Qi QI1, Xia LIU1, Shiyong LI1, Harish C JOSHI2, Keqiang YE1, *
1Department of Pathology and Laboratory Medicine, 2Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
Aim: Noscapine (NOS) is a non-narcotic opium alkaloid with anti-tumor activity. The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide (TMZ), bis-chloroethylnitrosourea (BCNU), or cisplatin (CIS)on human glioblastoma cells.
Methods: U87MG human glioblastoma cells were examined. Cell proliferation was quantified using MTT assay. Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP. Mouse tumor xenograft model bearing U87MG cells was treated with TMZ (2 mg·kg-1·d-1, ip) or CIS (2 mg/kg, ip 3 times a week) alone or in combination with NOS (200 mg·kg-1·d-1, ig) for 3 weeks. Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 following treatment in vivo. The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal’s organs.
Results: NOS (10 or 20 mol/L) markedly increased the anti-proliferation effects of TMZ, BCNU, and CIS on U87MG cells in vitro. The calculated combination index (CI) values of NOS-CIS, NOS-TMZ, and NOS-BCNU (20 μmol/L) were 0.45, 0.51, and 0.57, respectively, demonstrating synergistic inhibition of the drug combinations. In tumor xenograft models, combined treatment with NOS robustly augmented the anti-cancer actions of TMZ and CIS, and showed no detectable toxicity. The combined treatments significantly enhanced the apoptosis, the activated caspase-3 and PARP levels in U87MG cells in vitro, and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo.
Conclusion: NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells, thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.
Keywords: glioblastoma; noscapine; temozolamide; bis-chloroethylnitrosourea; cisplatin; apoptosis; caspase-3; tumor xenograft model; drug synergism
This project was funded with federal funds from the National Cancer Institute, National Institutes of Health, R01 (CA127119 to Keqiang YE). We thank Obiamaka OBIANYO for proofreading the manuscript.
* To whom correspondence should be addressed.
E-mail kye@emory.edu
Received 2012-12-25 Accepted 2013-03-21},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/7935}
}