Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth
Authors: Shiyong Li
Keqiang Ye
Xia Liu
Qi Qi
Harish C Joshi
Journal: Acta Pharmacologica Sinica (2013)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Noscapine; anti-tumor activity; chemotherapeutics; glioblastoma cells; apoptosis
Affiliations: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Abstract:  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 Œºmol/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. 

Retracted: No

PubPeer comments:
 I would like to point out to UK-based Nature Publishing Group that there are in fact guidelines for humane treatment of nude mice bearing tumourous xenograpfts. If I can find UK-based guidelines, why canu2019t NPG jobsworths? https: www.ncbi.nlm.nih.gov pmc articles PMC2883160 Now, either the depicted mice are very, very small or their tumours substantially exceed 1.5 cm. And please tell me those arenu2019t ulcerating necroses on the meeces 5, 6, 7 and 8 :-(  Edited 4-3-18 to spell xenograft correctly. It remains incorrect in the linked image. , 
 In Fig. 3D of this paper with those overgrown xenografts, two microscopy fields overlap but with different scaling. Note that TMZ is temozolamide whereas CIS is cisplatin so the labelled chemotherapeutics are different.  , 
 Letu2019s try again because there might be some confusion about the size of the xenografted tumours in the control mice. I am advised that, at Emory, the maximum acceptable tumour size is 20 mm in any length. If we assume that the xenografts have reached 2 cm in length, then we can get out our measuring stick and estimate the body size of the hosting mouse. The body length of these mice are then in the range of 4 - 5 cm as shown below. The problem here is that, in reality, adult mice are 7.5 - 10 cm in body length. https: en.wikipedia.org wiki House_mouse In practice, therefore, these mice are actually twice the size of the estimate when the tumours would be maximally 2 cm. Unfortunately, this means that the xenografts have actually been allowed to grow in size to 4 cm. This is double the ethical standard.  Two quotes from the **Emory University Tumor Burden Scoring Guidelines**: *Any individual tumor 20 mm in any dimension; Score=17* *Cumulative score 17 - Euthanasia is mandatoryu2026* ,