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Issue 41, 2013
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Combination of TNF-α and graphene oxide-loaded BEZ235 to enhance apoptosis of PIK3CA mutant colorectal cancer cells

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Abstract

The PI3K–AKT–mTOR pathway plays an important role in tumor cell growth, invasion, migration and apoptosis. A blockade of this signaling pathway has arisen as a compelling target for the tumor therapy. However, there is cross-talking between different signal pathways. Combined treatment of tumors with different signal pathway inhibitors is considered as an efficient strategy for cancer therapy. NVP-BEZ235 is a dual pan-class I PI3K and mTOR kinase inhibitor currently in clinical trial. TNF-α is involved in the regulation of cell apoptosis. In the current work, we explored the combined use of BEZ235 and TNF-α on the PIK3CA mutant colorectal cancer (CRC) cell proliferation inhibition. In our strategy, the BEZ235 is loaded on PEGylated graphene oxide (GO-PEG) by physisorption via π–π stacking to enhance its aqueous solubility. The resulting GO-BEZ235 complex exhibited excellent aqueous solubility while retaining a high cancer cell killing potency. The combination of BEZ235 and TNF-α shows an enhanced cellular proliferation inhibition for HCT 116 through enhancing the G1 phase arrest and cell apoptosis compared to either drug alone. Moreover, our experiments reveal that the enhanced tumor cell apoptosis depends on the activation of caspase-9, caspase-8 and caspase-3 mediated by the increased phosphorylation level of JNK. Taken together, our findings demonstrate for the first time the feasibility of BEZ235 delivered by GO-PEG and of the combined use of BEZ235 and TNF-α for PIK3CA mutant CRC therapy.

Graphical abstract: Combination of TNF-α and graphene oxide-loaded BEZ235 to enhance apoptosis of PIK3CA mutant colorectal cancer cells

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Supplementary files

Article information


Submitted
30 May 2013
Accepted
19 Aug 2013
First published
22 Aug 2013

J. Mater. Chem. B, 2013,1, 5602-5610
Article type
Paper

Combination of TNF-α and graphene oxide-loaded BEZ235 to enhance apoptosis of PIK3CA mutant colorectal cancer cells

Y. Cao, Y. Chong, H. Shen, M. Zhang, J. Huang, Y. Zhu and Z. Zhang, J. Mater. Chem. B, 2013, 1, 5602
DOI: 10.1039/C3TB20764A

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