Format

Send to

Choose Destination
J Neurooncol. 2016 Jan;126(2):253-64. doi: 10.1007/s11060-015-1972-1. Epub 2015 Dec 9.

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

Chang E1,2,3,4, Pohling C5,6,7,8, Natarajan A5,6,7,8, Witney TH5,6,7,8, Kaur J5,6,7,8, Xu L5,6,7,8, Gowrishankar G5,6,7,8, D'Souza AL5,6,7,8, Murty S5,6,7,8, Schick S5,6,7,8, Chen L5,6,7,8, Wu N5,6,7,8, Khaw P5,6,7,8, Mischel P9, Abbasi T10, Usmani S10, Mallick P5,6,7,8, Gambhir SS11,12,13,14.

Author information

1
Departments of Radiology and Bioengineering, Stanford University, Palo Alto, CA, USA. echangcv@stanford.edu.
2
Molecular Imaging Program at Stanford, Stanford University, Palo Alto, CA, USA. echangcv@stanford.edu.
3
Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA, USA. echangcv@stanford.edu.
4
Nuclear Medicine, Stanford University, Palo Alto, CA, USA. echangcv@stanford.edu.
5
Departments of Radiology and Bioengineering, Stanford University, Palo Alto, CA, USA.
6
Molecular Imaging Program at Stanford, Stanford University, Palo Alto, CA, USA.
7
Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA, USA.
8
Nuclear Medicine, Stanford University, Palo Alto, CA, USA.
9
Department of Medicine, Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA.
10
Cellworks Group Inc., San Jose, CA, USA.
11
Departments of Radiology and Bioengineering, Stanford University, Palo Alto, CA, USA. sgambhir@stanford.edu.
12
Molecular Imaging Program at Stanford, Stanford University, Palo Alto, CA, USA. sgambhir@stanford.edu.
13
Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA, USA. sgambhir@stanford.edu.
14
Nuclear Medicine, Stanford University, Palo Alto, CA, USA. sgambhir@stanford.edu.

Abstract

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.

KEYWORDS:

AshwaMAX; Bioluminescent; Glioblastoma; Preclinical; Withaferin A

PMID:
26650066
PMCID:
PMC5597337
DOI:
10.1007/s11060-015-1972-1
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center