Curcumin mediated down‐regulation of α_Vβ₃ integrin and up‐regulation of pyruvate dehydrogenase kinase 4 (PDK4) in Erlotinib resistant SW480 colon cancer cells

Abstract

Erlotinib is a potent, selective, and orally active inhibitor of the epidermal growth factor receptor, but the development of erlotinib resistance during chemotherapy can lead to treatment failure. To shed light on the erlotinib-resistant pathway, this study investigated the effect of combination therapy using curcumin- and erlotinib-loaded nanoparticles on the expression of α β integrin and pyruvate dehydrogenase kinase 4 (PDK4) in an erlotinib-resistant SW480 colon cancer cell line. An erlotinib-resistant SW480 colon cancer cell line was produced by long-term exposure to erlotinib. Curcumin-loaded Methoxy poly ethylene glycol Poly caprolactone (cur/mPEG-PCL) and erlotinib-loaded mPEG-PCL (erl/mPEG-PCL) micelles were provided using a single step nanoprecipitation method and used as combination therapy of resistant SW480 cancer cells. After that, gene expression levels of PDK4, αv, and β3 mRNA were determined by the semiquantitative reverse transcription-polymerase chain reaction. Protein levels of whole α β integrin were evaluated using the enzyme-linked immunosorbent assay method. In SW480 cell line, the IC50 of nonresistant and resistant cells was 87.6 ± 1.2 nM and 19.1 ± 0.14 μM, for erlotinib and it was about 21.8 and 30 μM for curcumin, respectively. Although PDK4 expression was not significantly different in resistant and nonresistant cells, its expression was up regulated (1.4 fold) in resistant cells by a combination therapy of cur/mPEG-PCL at a dose of 3 μM and erl/mPEG-PCL at a dose of 5 μM. β mRNA and the protein level of whole α β integrin was significantly higher in resistant SW480 cells as compared with those in nonresistant cells. In terms of treatment, a combination of 6-μM cur/mPEG-PCL and 5-μM erl/mPEG-PCL down regulated β gene expression 6.6-fold in resistant cells as compared with nonresistant cells. At the protein level, a combination of 3-μM-cur/mPEG-PCL and 10-μM erl/mPEG-PCL reduced α β protein in resistant cells. The results indicated that combination therapy using cur/mPEG-PCL and erl/mPEG-PCL could decrease α β integrin expression and increase PDK4 gene expression in resistant colon cancer cells, which may have effects on drug resistance signaling pathways.

Integrin as a Molecular Target for Anti-cancer Approaches in Lung Cancer

“…The disruption of integrin function caused a significant reduction in the activation of Akt and thereby decreased the levels of the migration promoting factor ENPP2 (50). In addition, curcumin is shown to be down-regulate integrin αvβ3 that could benefit to the treatment of erlotinib resistant colon cancer cells (51).…”

Electrospinning process parameters optimization for biofunctional curcumin/gelatin nanofibers

“…Curcumin is one of the components of turmeric. It has been shown that synthetic dimethoxycurcumin is more potent to destroy cancer (a leading cause of every sixth death worldwide) cells than natural curcumin (derived from the plant) [54][55][56][57][58][59][60][61][62][63][64]. Ramírezagudelo et al [55] incorporated antibiotic doxycycline drugs (inhibitors of mitochondrial biogenesis, could restrict cancer stem cells in initial breast cancer stages) into electrospun hybrid poly-caprolactone/gelatin/hydroxyapatite soft nanofibrous mats and evaluated these drug delivery meshes as effective anti-tumor and antibacterial scaffolds.…”

Curcumin sensitized the antitumour effects of irradiation in promoting apoptosis of oesophageal squamous-cell carcinoma through NF-κB signalling pathway

“…It has been widely used for therapeutic purpose histologically due to the intrinsic anti‐inflammatory, antioxidant and antitumour properties . The extensive investigations and exploitations have characterized the wide‐spectrum anticancer activity of curcumin against variety of human tumours including ovarian, breast, colon and so forth . The various modes of action have been proposed underlying its therapeutic function in treatment of human cancer, including inhibition of proliferation, induction of cell apoptosis and suppression of angiogenesis.…”

“…[14][15][16][17][18][19] The extensive investigations and exploitations have characterized the wide-spectrum anticancer activity of curcumin against variety of human tumours including ovarian, breast, colon and so forth. [20][21][22][23][24][25] The various modes of action have been proposed underlying its therapeutic function in treatment of human cancer, including inhibition of proliferation, induction of cell apoptosis and suppression of angiogenesis. However, the potential antitumour effect of curcumin against ESCC has not been extensively explored despite the sporadic reports conducted in immortalized human cancer cell lines.…”