Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells.

Abstract

Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM.

• Authors: Ning Wu, Jia Liu, Xiangzhong Zhao, Zhiyong Yan, Bo Jiang, Lijun Wang, Shousong Cao, Dayong Shi, Xiukun Lin
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 12 Pg. 9667-76 (Dec 2015) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26150336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chalcones
• Neoplasm Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• cardamonin

Topics

• Animals
• Apoptosis (drug effects)
• Catalytic Domain
• Cell Line, Tumor
• Chalcones (administration & dosage, chemistry)
• Drug Resistance, Neoplasm (genetics)
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Mice
• Molecular Docking Simulation
• Neoplasm Proteins (biosynthesis)
• Neoplastic Stem Cells (chemistry, drug effects, pathology)
• Protein Conformation (drug effects)
• STAT3 Transcription Factor (biosynthesis, chemistry)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays