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Cancer Lett. 2017 Jun 1;395:1-10. doi: 10.1016/j.canlet.2017.02.028. Epub 2017 Mar 1.

Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis.

Author information

1
Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3
Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea.
4
Thyroid Cancer Research Laboratory, Endocrine Surgery Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: sparangi@mgh.harvard.edu.

Abstract

Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line. In orthotopic thyroid cancer mouse models of 8505c and BCPAP, treatment with the triple drug combination reduced the size of the tumors and showed significantly higher numbers of cells undergoing apoptosis. This treatment increased the expression of pro-apoptotic protein Bim, while decreasing anti-apoptotic protein Mcl-1. Our results suggest that analyzing the results of BH3-profiling along with the mutational status of tumor can reveal an effective therapy for targeted, personalized treatment of aggressive thyroid cancer.

KEYWORDS:

Apoptosis; BRAF(V600E) inhibitor; Bcl2 family protein; Orthotopic model; Thyroid cancer

PMID:
28259821
DOI:
10.1016/j.canlet.2017.02.028
[Indexed for MEDLINE]

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