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Toxicol In Vitro. 2018 Oct;52:306-313. doi: 10.1016/j.tiv.2018.07.001. Epub 2018 Jul 9.

Verapamil potentiates anti-glioblastoma efficacy of temozolomide by modulating apoptotic signaling.

Author information

1
Institute of Biomedical Sciences, Dow University of Health Sciences, Ojha Campus, SUPARCO Road, Karachi, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. Electronic address: farina.hanif@duhs.edu.pk.
2
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Department of Biochemistry, Baqai Medical University, Karachi, Pakistan.
3
Institute of Biomedical Sciences, Dow University of Health Sciences, Ojha Campus, SUPARCO Road, Karachi, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. Electronic address: saima.mahmood@duhs.edu.pk.
4
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Mohammad Ali Jinnah University, Karachi, Pakistan.
5
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. Electronic address: shabana.simjee@iccs.edu.

Abstract

Glioblastoma Multiforme (GBM) is the most malignant and invasive tumor of the CNS. Although temozolomide (TMZ) has improved the survival, long-lasting responses have not been reported. Therefore, there is a need to develop improved treatments, one of which might be newly identified drugs which can be used in combination therapy with low doses of standard drugs. Verapamil (VP) a known antihypertensive drug has been shown to enhance the activity of bis-chloroethylnitrosourea (BCNU), a drug used to treat GBM. Since, TMZ has replaced BCNU as the standard GBM chemotherapy; therefore, we aimed to study in vitro interaction of VP and TMZ against GBM. Anti-proliferative and apoptotic activities were studied using MTT, TUNEL assay and DAPI staining. Synergy was assessed using combination index method. Apoptotic markers were evaluated by RT-PCR, and immunocytochemistry. Both VP and TMZ significantly inhibited the growth of U87 cells in dose dependent manner. The combine effect of TMZ with VP was synergistic with a CDI value of <1. Combination of TMZ and VP increased the ratio of Bax to Bcl-2 expression and thus shifted the equilibrium of cells towards apoptosis. Our findings suggest that the synergistic growth inhibition that was observed in combination treatment group may in part relate to increase in apoptosis. The combine administration of VP and TMZ may be therapeutically exploited for the management of GBM.

KEYWORDS:

Apoptosis; Glioblastoma; Temozolmide; Verapamil

PMID:
30003979
DOI:
10.1016/j.tiv.2018.07.001
[Indexed for MEDLINE]

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