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

Tung-Cheng Chang; Yu-Tang Chin; André Wendindondé Nana; Shwu-Huey Wang; Yu-Min Liao; Yi-Ru Chen; Ya-Jung Shih; Chun A Changou; Yu-Chen Sh Yang; Kuan Wang; Jacqueline Whang-Peng; Liang-Shun Wang; Steven C Stain; Ai Shih; Hung-Yun Lin; Chih-Hsiung Wu; Paul J Davis

doi:10.1007/s12672-018-0341-x

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

Horm Cancer. 2018 Dec;9(6):420-432. doi: 10.1007/s12672-018-0341-x. Epub 2018 Sep 5.

Authors

Tung-Cheng Chang^{1

2

3}, Yu-Tang Chin^{4

5}, André Wendindondé Nana⁵, Shwu-Huey Wang^{6

7}, Yu-Min Liao⁸, Yi-Ru Chen^{4

5}, Ya-Jung Shih^{4

5}, Chun A Changou^{5

6

9}, Yu-Chen Sh Yang¹⁰, Kuan Wang¹¹, Jacqueline Whang-Peng¹², Liang-Shun Wang^{1

13}, Steven C Stain¹⁴, Ai Shih¹⁵, Hung-Yun Lin^{16

17

18

19

20}, Chih-Hsiung Wu^{21

22}, Paul J Davis^{23

24

25}

Affiliations

¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
² Division of Colorectal Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan.
³ Division of Colorectal Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁴ Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan.
⁵ The PhD program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁶ Core Facility Center, Office of Research and Development, Taipei Medical University, Taipei, 11031, Taiwan.
⁷ Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁸ Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, 11031, Taiwan.
⁹ Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
¹⁰ Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, 11031, Taiwan.
¹¹ Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei, 11031, Taiwan.
¹² Taipei Cancer Center; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
¹³ Department of Surgery, Shuang Ho Hospital, Taipei Medical University, No. 291, Zhongzheng Rd., Zhonghe, New Taipei City, 23561, Taiwan.
¹⁴ Department of Surgery, Albany Medical College, Albany, NY, 12208, USA.
¹⁵ National Laboratory Animal Center, Taipei, 11599, Taiwan.
¹⁶ Taipei Cancer Center, Taipei Medical University, Taipei, 11031, Taiwan. [email protected].
¹⁷ The PhD program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
¹⁸ Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, 12144, USA. [email protected].
¹⁹ Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. [email protected].
²⁰ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan. [email protected].
²¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. [email protected].
²² Department of Surgery, Shuang Ho Hospital, Taipei Medical University, No. 291, Zhongzheng Rd., Zhonghe, New Taipei City, 23561, Taiwan. [email protected].
²³ Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, 12144, USA. [email protected].
²⁴ NanoPharmaceuticals LLC, Rensselaer, NY, 12144, USA. [email protected].
²⁵ Department of Medicine, Albany Medical College, Albany, NY, 12208, USA. [email protected].

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. β-Galactoside α-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Colorectal Neoplasms / pathology*
Enzyme Activation / drug effects
ErbB Receptors / drug effects
ErbB Receptors / metabolism
Gefitinib / pharmacology*
HCT116 Cells
HT29 Cells
Humans
Mice
Mice, Nude
Phosphatidylinositol 3-Kinases / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Polyglactin 910 / pharmacology*
Thyroxine / analogs & derivatives*
Thyroxine / pharmacology
Xenograft Model Antitumor Assays

Substances

nano-diamino-tetrac
Polyglactin 910
Phosphatidylinositol 3-Kinases
EGFR protein, human
ErbB Receptors
Thyroxine
Gefitinib