الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most prevalent neoplastic malignancy in females worldwide, and even though the enhancements in standard therapies have improved survival rates during the previous 20 years, not all cases benefit from presently existing treatments. Numerous studies have been conducted on treatments for patients with breast cancer. Therefore, it is essential to find new therapies that can lower breast cancer mortality rates. Conventional therapy does not kill all tumor cells and a small side population of cells, which are resistant to radiation and drugs, might be the origin of recurrence and metastasis. Sorafenib (SOR) is a multi-kinase inhibitor targeting Raf/MEK/ERK, VEGF receptors, along with platelet-derived growth factor receptor signaling pathways. One of the more challenging disadvantages in the clinical application of SOR is its serious side effects including diarrhea, hypertension and hand-foot skin reaction (HFSR) which result in a dose reduction or discontinuation of SOR treatment in many breast cancer patients. Because two phase-II trials revealed that monotherapy with SOR is ineffective in clinical settings, the combination of SOR with other drugs is still the only way for investigation. HFSR is the most common side effect of SOR, and its pathogenesis is not fully understood, as it may be due to injured deep capillaries in the feet and palms of the hands, leading to a COX inflammatory-type reaction. Several clinicians consider that HFSR is a type of inflammation limited to the hands and feet and can be blocked with a COX-2 inhibitor. Thus, we propose combining of SOR with CEL might be beneficial in TNBC upon further preclinical assessment.
We investigated the effects of combining the non-steroidal anti-inflammatory, Celecoxib (CEL) with Sorafenib (SOR) on breast cancer cells. Estrogen receptor positive cells, MCF-7 and triple negative, MBA-MB-231 breast cancer cell lines were used for the study. Our results indicate dose dependent cytotoxicity of CEL or SOR in breast cancer cells lines, and synergistic effect of the combination of CEL+SOR on the viability and migration of breast cancer cells. CEL enhanced SOR-induced apoptosis and inhibition of ERK phosphorylation, and CEL inhibited PGE2 protein expression in cells treated with SOR. Interestingly, CEL decreased the expression of P65 and TNF-a and inhibited NF-kB target genes, ICAM1 and RELB, suggesting alleviating inflammation in sorafenib treated cells. Results collectively suggest that the combination of nonsteroidal anti-inflammatory, CEL with ERK inhibition, SOR have synergistic anti-tumor activity on TNBC cells.
This study suggests the synergy between SOR and CEL in TNBC cells and thus provides proof of concept for a treatment strategy that could enhance the efficacy and potency of SOR and decrease its side effects in the clinic. SOR at clinically effective doses causes adverse effects that reduce quality of life, including high rates of diarrhea and HFSR. Reducing the required dose of SOR by combining it with CEL may diminish side-effects associated with its use in TNBC.
As our study focused on the in-vitro investigations only, our recommendations are to further explore if the same combination ratio could result in the same synergistic interactions in the in vivo models and further clinical trials accordingly.