Dual targeting of glioblastoma multiforme with a proteasome inhibitor (Velcade) and a phosphatidylinositol 3-kinase inhibitor (ZSTK474)
- Authors:
- Lehang Lin
- Daria Gaut
- Kaishun Hu
- Haiyan Yan
- Dong Yin
- H. Phillip Koeffler
View Affiliations
Affiliations: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China, Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA
- Published online on: December 2, 2013 https://doi.org/10.3892/ijo.2013.2205
-
Pages:
557-562
Metrics: Total
Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
This article is mentioned in:
Abstract
Proteasome inhibitors have been proven to be effective anticancer compounds in many tumor models, including glioblastoma multiforme (GBM). In this study, we found that the proteasome inhibitor Velcade (PS-341/bortezomib) caused GBM cell death while simultaneously activating the PI3K/Akt pathway. Therefore, we sought to investigate if the PI3K inhibitor ZSTK474 would enhance the effectiveness of Velcade in anticancer therapy. Two GBM cell lines were used to detect the effects of Velcade and ZSTK474 alone or in combination in vitro. The combination of Velcade and ZSTK474 synergistically inhibited the proliferation of GBM cell lines. Cell apoptosis was increased when exposed to Velcade and ZSTK474 in combination as shown by Annexin V analysis. Treatment with both drugs led to downregulation of the p-Akt, p-4EBP1 and p-mTOR proteins as determined by western blot analysis. The anticancer ability of Velcade for glioblastoma multiforme was, therefore, enhanced by combination with the PI3K pathway inhibitor ZSTK474 in glioblastoma multiforme.
View References
1.
|
Adams J, Palombella VJ and Elliott PJ:
Proteasome inhibition: a new strategy in cancer treatment. Invest
New Drugs. 18:109–121. 2000. View Article : Google Scholar : PubMed/NCBI
|
2.
|
Yamamura M, Hirai T and Yamaguchi Y:
Proteasome inhibitor. Nihon Rinsho. 68:1079–1084. 2010.(In
Japanese).
|
3.
|
Chen D, Frezza M, Schmitt S, Kanwar J and
Dou QP: Bortezomib as the first proteasome inhibitor anticancer
drug: current status and future perspectives. Curr Cancer Drug
Targets. 11:239–253. 2011. View Article : Google Scholar : PubMed/NCBI
|
4.
|
Yin D, Zhou H, Kumagai T, et al:
Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis
in human glioblastoma multiforme (GBM). Oncogene. 24:344–354. 2005.
View Article : Google Scholar : PubMed/NCBI
|
5.
|
Mischel PS and Cloughesy TF: Targeted
molecular therapy of GBM. Brain Pathol. 13:52–61. 2003. View Article : Google Scholar : PubMed/NCBI
|
6.
|
Vivanco I and Sawyers CL: The
phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev
Cancer. 2:489–501. 2002. View
Article : Google Scholar : PubMed/NCBI
|
7.
|
Samuels Y, Wang Z, Bardelli A, et al: High
frequency of mutations of the PIK3CA gene in human cancers.
Science. 304:5542004. View Article : Google Scholar : PubMed/NCBI
|
8.
|
Shayesteh L, Lu Y, Kuo WL, et al: PIK3CA
is implicated as an oncogene in ovarian cancer. Nat Genet.
21:99–102. 1999. View
Article : Google Scholar : PubMed/NCBI
|
9.
|
Krakstad C and Chekenya M: Survival
signalling and apoptosis resistance in glioblastomas: opportunities
for targeted therapeutics. Mol Cancer. 9:1352010. View Article : Google Scholar : PubMed/NCBI
|
10.
|
Chakravarti A, Zhai G, Suzuki Y, et al:
The prognostic significance of phosphatidylinositol 3-kinase
pathway activation in human gliomas. J Clin Oncol. 22:1926–1933.
2004. View Article : Google Scholar : PubMed/NCBI
|
11.
|
Ruggeri B, Miknyoczki S, Dorsey B and Hui
AM: The development and pharmacology of proteasome inhibitors for
the management and treatment of cancer. Adv Pharmacol. 57:91–135.
2009. View Article : Google Scholar : PubMed/NCBI
|
12.
|
Luo J, Manning BD and Cantley LC:
Targeting the PI3K-Akt pathway in human cancer: rationale and
promise. Cancer Cell. 4:257–262. 2003. View Article : Google Scholar : PubMed/NCBI
|
13.
|
Dan S, Yoshimi H, Okamura M, Mukai Y and
Yamori T: Inhibition of PI3K by ZSTK474 suppressed tumor growth not
via apoptosis but G0/G1 arrest. Biochem Biophys Res Commun.
379:104–109. 2009. View Article : Google Scholar : PubMed/NCBI
|
14.
|
Kong D and Yamori T: Advances in
development of phosphatidylinositol 3-kinase inhibitors. Curr Med
Chem. 16:2839–2854. 2009. View Article : Google Scholar : PubMed/NCBI
|