الفهرس 
Title : Effect of valproic acid on the anti-tumor activity of methotrexate in breast cancer
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Abstract
Breast Cancer (BC) is the most common type of cancer impacting
millions of women yearly causing the greatest cancer-related deaths rate
among women worldwide. Histone deacetylase inhibitors (HDACIs) are a
promising class of drugs that act as antiproliferative agents by promoting
differentiation and inducing apoptosis. Valproic acid (VPA) is a HDACI that
has been widely used as an anti-convulsant and shows a promising effect as a
chemotherapeutic drug for a number of tumor cells. Most studies have showed
the use of methotrexate (MTX) in cancer chemotherapy due to its ability to
block the de novo synthesis of purines and pyrimidines by irreversibly
inhibiting the enzyme dihydrofolate reductase (DHFR) which is responsible
for the production of tetrahydrofolate. Chemotherapy with MTX can reach
very high doses that are responsible for the serious side effects such as
nephrotoxicity. The present study aimed to investigate the inhibitory effect of
VPA on the viability of mammary cancer cells and its enhancing effect with
MTX chemotherapeutic effect in vitro and in vivo. The cell viability of human
breast cancer cell lines following treatment with VPA and/or MTX in were
determined using a sulphorhodamine B assay. Treatments with MTX or VPA
alone induced concentration-dependent cytotoxic effects in the two breast
cancer cell lines used MCF7 and MDA-MB231. The two concentrations used
of VPA (1.562 and 3.125 mM), increased significantly the cytotoxicity of
MTX (3 & 2.8 times), respectively, against MCF7 with no significant
difference between the two concentrations of VPA. In the contrary, VPA
addition to MTX did not produce any significant changes on MTX
cytotoxicity against MDA-MB231. Methotrexate was found to be slightly
2
more effective on MDA-MB231 than MCF7. The in vivo tumor growth
inhibition of VPA was determined in mice with Ehrlich ascites carcinoma
(EAC) and solid Ehrlich carcinoma (SEC) models. Valproic acid (200 and
150 mg/kg) significantly inhibited the growth of EAC as well as SEC,
respectively, in albino female mice models and improved results were
achieved for tumor inhibition when VPA was combined with MTX (1 and 2
mg/kg) in vivo. Lowering the doses of MTX and VPA in combination reduced
mice toxicity and still showed antitumor activity. All our study findings
suggest that the combination of MTX and VPA may have clinical and/or
adjuvant therapeutic application in the treatment of mammary cancer. A
finding that needs confirmation in the clinical setting.