Deregulation of EGFR/PI3K and activation of PTEN by photodynamic therapy combined with carboplatin in human anaplastic thyroid cancer cells and xenograft tumors in nude mice

Abstract

Phosphatidylinositol-3-kinase (PI3K) is one of the major activated pathways involved in the progression of anaplastic thyroid cancer. The activated PI3K pathway starts from the overexpression of epidermal growth-factor receptor (EGFR) which plays a key role in cancer development and metastasis. However, a protein, PTEN negatively regulates the PI3K pathway. Here we studied the possibility of using a combination of conventional chemotherapy and photodynamic therapy to inhibit the growth of human anaplastic thyroid cancer in vitro and in vivo. Carboplatin (CBDCA) and radachlorin-photodynamic therapy (PDT) were used for the combination treatment of human anaplastic thyroid cancer cells FRO and tumor xenograft in athymic mice. Confocal microscopic and flow cytometric observations showed that cell death was mainly through an enhanced apoptosis with the combination of CBDCA and PDT. Generation of reactive oxygen species and dysfunction of mitochondrial membranes suggested that the enhanced apoptosis was achieved through the mitochondrial cell death pathway. This was confirmed by Western blot analysis of caspase 3, 9 expressions. Further analysis showed that the combination of CBDCA and PDT inhibited the expression of EGFR and PI3K with higher efficacy. PTEN also was activated more in this combination group. This suggests a combination of CBDCA and PDT modulates EGFR and PI3K as well as activates PTEN to inhibit tumor growth and induce apoptosis with an enhanced efficacy in anaplastic thyroid cancer.