Dataset Information

Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation.

ABSTRACT: Drug resistance complicates the clinical use of gefitinib. Tetraiodothyroacetic acid (tetrac) and nano-diamino-tetrac (NDAT) have been shown in vitro and in xenografts to have antiproliferative/angiogenic properties and to potentiate antiproliferative activity of other anticancer agents. In the current study, we investigated the effects of NDAT on the anticancer activities of gefitinib in human colorectal cancer cells. ?-Galactoside ?-2,6-sialyltransferase 1 (ST6Gal1) catalyzes EGFR sialylation that is associated with gefitinib resistance in colorectal cancers, and this was also investigated. Gefitinib inhibited cell proliferation of HT-29 cells (K-ras wild-type), and NDAT significantly enhanced the antiproliferative action of gefitinib. Gefitinib inhibited cell proliferation of HCT116 cells (K-ras mutant) only in high concentration, and this was further enhanced by NDAT. NDAT enhancedd gefitinib-induced antiproliferation in gefitinib-resistant colorectal cancer cells by inhibiting ST6Gal1 activity and PI3K activation. Furthermore, NDAT enhanced gefitinib-induced anticancer activity additively in colorectal cancer HCT116 cell xenograft-bearing nude mice. Results suggest that NDAT may have an application with gefitinib as combination colorectal cancer therapy.

SUBMITTER: Chang TC

PROVIDER: S-EPMC6223990 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation.

Chang Tung-Cheng TC Chin Yu-Tang YT Nana André Wendindondé AW Wang Shwu-Huey SH Liao Yu-Min YM Chen Yi-Ru YR Shih Ya-Jung YJ Changou Chun A CA Yang Yu-Chen Sh YS Wang Kuan K Whang-Peng Jacqueline J Wang Liang-Shun LS Stain Steven C SC Shih Ai A Lin Hung-Yun HY Wu Chih-Hsiung CH Davis Paul J PJ

Hormones & cancer 20180905 6

Drug resistance complicates the clinical use of gefitinib. Tetraiodothyroacetic acid (tetrac) and nano-diamino-tetrac (NDAT) have been shown in vitro and in xenografts to have antiproliferative/angiogenic properties and to potentiate antiproliferative activity of other anticancer agents. In the current study, we investigated the effects of NDAT on the anticancer activities of gefitinib in human colorectal cancer cells. β-Galactoside α-2,6-sialyltransferase 1 (ST6Gal1) catalyzes EGFR sialylation ...[more]

PMID: 30187356

Similar Datasets

Project description:BackgroundNon-small cell lung cancer (NSCLC) expressed high levels of epidermal growth factor receptor (EGFR). Gefitinib (Iressa) has demonstrated clinical efficacy in NSCLC patients harboring EGFR mutations or refractory to chemotherapy. However, most of NSCLC patients are with wild type EGFR, and showed limited response to gefitinib. Therefore, to develop new effective therapeutic interventions for NSCLC is still required. Our previous study showed Marsdenia tenacissima extract (MTE) restored gefitinib efficacy in the resistant NSCLC cells, but whether MTE acts in the gefitinib-sensitive NSCLC cells is the same as it in the resistant one is unknown.MethodsDose response curves for gefitinib and MTE were generated for two sensitive NSCLC cell lines with mutant or wild type EGFR status. Three different sequential combinations of MTE and gefitinib on cell growth were evaluated using IC50 and Combination Index approaches. The flow cytometric method was used to detect cell apoptosis and cell cycle profile. The impact of MTE combined with gefitinib on cell molecular network response was studied by Western blotting.ResultsUnlike in the resistant NSCLC cells, our results revealed that low cytotoxic dose of MTE (8 mg/ml) combined gefitinib with three different schedules synergistically or additively enhanced the growth inhibition of gefitinib. Among which, MTE→MTE+gefitinib treatment was the most effective one. MTE markedly prompted cell cycle arrest and apoptosis caused by gefitinib both in EGFR mutant (HCC827) and wild type of NSCLC cells (H292). The Western blotting results showed that MTE→MTE+gefitinib treatment further enhanced the suppression of gefitinib on cell growth and apoptosis pathway such as ERK1/2 and PI3K/Akt/mTOR. This combination also blocked the activation of EGFR and c-Met which have cross-talk with each other. Unlike in gefitinib-resistant NSCLC cells, MTE alone also demonstrated certain unexpected modulation on EGFR related cell signal pathways in the sensitive cells.ConclusionOur results suggest that MTE is a promising herbal medicine to improve gefitinib efficacy in NSCLC regardless of EGFR status. However, why MTE acted differently between gefitinib-sensitive and -resistant NSCLC cells needs a further research.

Project description:Heatmap, pathway scores and significant modulation of genes induced by heteronemin, tetrac, and their combination versus the control in HCT 116 cells were performed. (abstract) Overexpression of EGFR accounts for 60-80% of colorectal cancer patients. Anti-EGFR monoclonal antibodies are ineffective in colorectal cancer patients due to KRAS mutation. To discover new therapeutic strategies urgently need for colorectal cancer patients. Sponge extract, heteronemin, has been shown to induce anti-proliferation in different types of cancer. Tetrac shows to inhibit Ras-mutant cancer cell proliferation. Cell viability was evaluated in the HT-29 and HCT-116 cell lines to determine the antitumor effects of heteronemin and its combination with tetrac. Gene expressions were determined by NanoString technology and a quantitative RT-PCR. Protein expressions and cell cycle distributions were respectively assessed by Western blotting and flow cytometry. Heteronemin or its combination with tetrac inhibited cancer cell growth in both mutant and KRAS wild-type CRC. Combined treatment altered the cell cycle in both cell lines at the sub-G1 and S phases. Moreover, their combination induced inactivation of EGFR signaling via downregulating the phosphorylated and total extracellular signal-regulated kinase 1/2 (ERK1/2) protein in both cell lines. The programmed death ligand 1 (PD-L1) protein was reduced in HCT-116 cells, while HT-29 cells showed downregulation of the phosphorylated and total phosphatidylinositol 3-kinase (PI3K) protein. In KRAS mutant cells, heteronemin or its combination with tetrac showed significant modulation of genes associated with cancer progression by NanoString technology. Therefore, tetrac improved the anticancer effect of heteronemin and may be an alternative strategy to effective overcome KRAS mutation-acquired resistance to anti-EGFR therapy. 1. To investigate whether heteronemin combined tetrac induce the antitumor effect in different KRAS statuses of CRC via blocking of EGFR signaling cascades. 2. To assess gene expression profiling in KRAS-mutant CRC cells by nanostring technology.

Dataset Information

Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation.

Publications

Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets