Abstract
Glioblastoma multiforme (GBM) is the most common and deadly brain cancer, characterized by its aggressive proliferation to adjacent tissue and high recurrence rate. We studied the efficacy and related mechanisms of the combination of cyclopamine (Cyp, a Sonic-hedgehog pathway (Shh) inhibitor) and temozolomide (TMZ, the clinically most used chemotherapeutic agent) in anti-GBM treatment. The micellarized Cyp (MCyp) showed better performance than Cyp solution in inhibiting GBM cells proliferation (3.77-fold against U87 MG cells and 3.28-fold against DBTRG-05MG cells) and clonogenity (1.35-fold against U87 MG cells and 2.17-fold against DBTRG-05MG cells), and preferred behavior of inhibiting cell invasion, colony formation through attenuated Gli1 expression. In addition, combination of MCyp and TMZ exhibited synergistic cytotoxicity, correlating with their ability in inducing apoptosis and eliminating neurospheres formation, and the combination of TMZ was accompanied with the enhanced blockage of Shh pathway. The optimal ratio of MCyp combined to TMZ was 1:20. So we proposed to use TMZ to kill tumor parenchyma and MCyp as the cancer stem cells inhibitor to resist tumor recurrence. These findings demonstrated that combination of TMZ with micellarized Cyp is a promising strategy for exerting different functions of drugs for tumor treatment.
Highlights
Glioblastoma (GBM) is one of the most dangerous cancers and is among the most aggressive cancers [1]
Our results suggest the additive efficacy of micellarized Cyp (MCyp) and TMZ in Glioblastoma multiforme (GBM) cells is suitable for bulk tumors
As the most effective first-line drugs in clinical treatment of glioma, TMZ is very effective in eliminating tumor parenchyma as well as being able to cross the bloodbrain barrier (BBB)
Summary
Glioblastoma (GBM) is one of the most dangerous cancers and is among the most aggressive cancers [1]. GBM cells invade and migrate along white matter tracts [2] and blood vessels [3]. The first choice of GBM treatment is surgical resection. The recurrence of GBM becomes unavoidable which reduces patients’ life expectation to less than one year [5, 6]. Chemotherapy becomes a vital part in GBM treatment. Traditional drug therapy is significantly impaired by bloodbrain barrier (BBB) and efflux transport proteins (P-gp). A majority of drugs that show great anti-tumor potential in vitro, yield little efficacy in vivo. With the pharmacological intervention, the medium living period of the GBM patients is only 14.6 months
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