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.
Subject(s)
Brain Neoplasms/metabolism , Dacarbazine/analogs & derivatives , Glioblastoma/metabolism , Micelles , Veratrum Alkaloids/administration & dosage , Zinc Finger Protein GLI1/metabolism , Apoptosis/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dacarbazine/administration & dosage , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Signal Transduction/drug effects , Temozolomide , Tumor Stem Cell Assay , Zinc Finger Protein GLI1/geneticsABSTRACT
A new phenylpropanoid glucoside tuberosinine D (1) and a chain compound (Z)-11R,12S,13S-trihydroxy-9-octadecenoate (2) were isolated from the roots of Allium tuberosum. The absolute configuration of 1 was established by comparing of experimental and calculated electronic circular dichroism. The absolute configuration of 2 was determined using the modiï¬ed Mosher's method for the first time.
