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| Type |
Poster Presentation |
| Area |
Life Chemistry |
| Room No. |
Grand Ballroom |
| Time |
10월 19일 (금요일) 11:00~12:30 |
| Code |
LIFE.P-440 |
| Subject |
Synergistic Anticancer Effects of the Receptor Tyrosine Kinase Inhibitor Vandetanib and SHP2 inhibitor (Polyphyllin D) on T-cell Acute Lymphoblastic Leukemia Cell Lines |
| Authors |
Se Jeong Kwon, Sang Jeon Chung*
College of Pharmacy, SungKyunKwan University, Korea
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| Abstract |
FDA-approved vandetanib is a small-molecule receptor tyrosine kinase (RTK) inhibitor that is used in cancer treatment. However, resistance to vandetanib can be developed within a few years, resulting in cancer relapse. SHP2 promotes the activation of RAS by regulating signaling upstream of Ras and is a key mediator of programmed cell death 1 and B- and T-lymphocyte attenuator immune checkpoint pathways. Based on the involvement of SHP2 and RTK in cell proliferation, we hypothesized that simultaneous inhibition of SHP2 and RTK could result in a potent anticancer effect overcoming cellular resistance to vandetanib. However, the majority of SHP2 inhibitors suffer from poor selectivity as they also target various other protein tyrosine phosphatases (PTPs), presumably due to the highly conserved active site of PTPs. To search SHP2 inhibitors, we screened 658 phytochemicals to identify many natural product SHP2 inhibitors with strong inhibitory activity, however only polyphyllin D showed inhibitory selectivity to SHP2 over other PTPs although their inhibitory activities are moderate (Ki = 64.2, 66.5µM). Furthermore, T-cell acute lymphoblastic leukemia cell lines were treated with vandetanib and the selected SHP2 inhibitors. Combination index values were determined to demonstrate that vandetanib and SHP2 inhibitor show synergistic inhibition of cancer cell growth. Increase in PARP cleavage and caspase-3 activation was observed, meaning that the combination of vandetanib and SHP2 inhibitors induce stronger cancer cell apoptosis in the signal associated with ERK, AKT, Bcl2.
Keywords: Vandetanib; receptor protein kinases; SHP2; T-ALL; apoptosis; cancer treatment; synergistic; combined treatment
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| E-mail |
sejung1110@naver.com |
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122nd General Meeting of the KCS