Modulation of Plasma 25-Hydroxyvitamin D3 Level by Imatinib Mesylate in Patients with Chronic Myelogenous Leukemia: The Role of Uptake and Efflux Transporters.

Background: Vitamin D deficiency is a common side effect of imatinib mesylate (IM) therapy. Transporter polypeptides involved in the disposition of IM may be required for maintenance of adequate vitamin D concentrations. Objective: The aim of the present work is to study the association between the plasma concentrations of IM and plasma 25-hydroxyvitamin (25[OH]) D3 with transporter genotypes in patients with chronic myelogenous leukemia. Methods: A total of 77 adult patients with chronic myelogenous leukemia treated with IM participated in this study. Peak and trough plasma IM and 25(OH) vitamin D3 concentrations were measured and compared to the results of single nucleotide polymorphisms of the efflux transporting gene ABCB1-1236 C>T and the uptake transporting gene OATP1B3-334 T>G. Multiple linear regressions were used to examine the associations between 25(OH) vitamin D3 concentrations and a number of patient characteristics, including responses to therapy. Binary logistic regression analysis was used to predict odd ratios for the clinical response to IM. Results: Plasma 25(OH) vitamin D3 concentration quartile values were: 25%, 8.2 ng/mL; 50%, 9.8 ng/mL; and 75%, 12 ng/mL. High IM peak concentration, being OATP1B3-334 T>G (TT), and/ or ABCB1-1236 C>T (CT) are associated with lower concentrations of 25(OH) vitamin D3. Moreover, IM peak concentration, IM trough concentration, and plasma concentration of 25(OH) vitamin D3 were associated with the clinical response to IM. Conclusions: vitamin D, IM concentration, as well as the genotype of OATP1B3-334 T>G, had an influence on the response of patients with chronic myelogenous leukemia.

Thymoquinone chemosensitizes human colorectal cancer cells to imatinib via uptake/efflux genes modulation.

Imatinib (IM) is a pharmaceutical drug that inhibits tyrosine kinase enzymes that are responsible for the activation of many proteins by signal transduction cascades as c-Abl, c-Kit and the platelet-derived growth factor (PDGF) receptor. Thymoquinone (TQ) is an active constituent of Nigella sativa seeds. Thymoquinone benefits are attributed to its medicinal uses as antioxidant, anticancer and antimicrobial agent. This study aimed to investigate the impact of using TQ with IM in the HCT116 human colorectal cancer cell line model. The HCT116 cells were treated with IM or/and TQ in non-constant ratios, in which the fixed concentrations of TQ (5, 10 or 20 µmol/L) were co-treated with various concentrations of IM (7.5-120 µmol/L) for 24, 48 and 72 hours. Imatinib-TQ interaction was analysed using CompuSyn software. The IC50 values for IM were 105, 72 µmol/L after 48 and 72 hours, respectively, and were significantly reduced to 7.3, 7 and 5.5 µmol/L after combination with TQ (10 µmol/L) and to 5.8, 5.6 and 4.6 µmol/L after combination with TQ (20 µmol/L) to 24, 48 and 72 hours, respectively. The combination index (CI) and dose reduction index (DRI) values indicate a significant synergism in HCT-116 cells at different treatment time points. Thymoquinone significantly enhances the cellular uptake of IM in HCT116 cells in a time and concentration-dependent manner. A significant downregulation in ATP-binding cassette (ABC) subfamily B member 1 (ABCB1), ABC subfamily G member 2 (ABCG2) and human organic cation transporter 1 (hOCT1) genes was observed in the cells exposed to IM+TQ combination as compared to IM alone, which resulted in a substantial elevation in uptake/efflux ratio in combination group. In conclusion, TQ potentiates IM efficacy on HCT116 cells via uptake/efflux genes modulation.

Suppression of macrophages- Induced inflammation via targeting RAS and PAR-4 signaling in breast cancer cell lines.

Tumor associated macrophages (TAMs) have a crucial role in cancer progression, metastasis and drug response. Piroxicam and sulindac sulfide are non-steroidal anti-inflammatory drugs (NSAID) that decrease the incidence and progression of several types of cancer. However, their role in suppressing the interactions between TAMs and cancer cells remain unclear. Herein, we studied the impact of human monocytes conditioned media (CM) on cellular proliferation of ER-dependent MCF-7 and ER-independent MDA-MB-231 cells, and the effects of piroxicam and sulindac sulfide on the expression levels of RAS, COX-2, IL-6, IL-1ß and PAR-4 (qRT-PCR), BCL-2 and BAX (western blot), Caspase-3, VEGF-a and PGE2 (ELISA), MMP-2 and -9 (zymography) in the stimulated cells. Our results showed that CM caused a significant increase in cells survival through significant increase in RAS expression which resulted in upregulation of COX-2, PGE2, BCL-2, IL-6, IL-1ß, VEGF-A and MMP-9 and down regulation of PAR-4. Treatment with one of the NSAIDs used in this study produced a time and concentration dependent growth inhibition of stimulated cells by inhibiting RAS expression. Suppression of RAS was accompanied by downregulation of its downstream signaling of IL-1ß, IL-6, COX-2 and PGE2, activation of apoptotic machinery through upregulation of PAR-4 and caspase-3, as well as, inhibition of BCL-2, VEGF-A, MMP-2 and MMP-9. In conclusion, our data support the role of piroxicam and sulindac sulfide in suppressing inflammation-driven breast cancer progression and identifies promising novel target in RAS and PAR-4 signaling.