Valproic acid enhances bosutinib cytotoxicity in colon cancer cells.

Rich66 · 06-06-2009, 07:05 PM

1: Int J Cancer. 2009 Apr 15;124(8):1990-6. Links: Valproic acid enhances bosutinib cytotoxicity in colon cancer cells.

Mologni L, Cleris L, Magistroni V, Piazza R, Boschelli F, Formelli F, Gambacorti-Passerini C.
Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy. luca.mologni@unimib.it
Unbalanced histone deacetylase (HDAC) hyperactivity is a common feature of tumor cells. Inhibition of HDAC activity is often associated with cancer cell growth impairment and death. Valproic acid (VPA) is a HDAC inhibitor used for the treatment of epilepsy. It has recently been recognized as a promising anticancer drug. We investigated the effects of VPA on growth and survival of colon cancer cells. VPA caused growth inhibition and programmed cell death that correlated with histone hyperacetylation. VPA modulated the expression of various factors involved in cell cycle control and apoptosis and induced caspase activation. Interestingly, VPA induced downregulation of c-Src and potentiated the cytotoxic effects of the c-Src inhibitor bosutinib, both in vitro and in vivo. The combination of sublethal doses of VPA and bosutinib led to massive apoptosis of colon cancer cells, irrespective of their genetic background. These results suggest that VPA may be employed as a positive modulator of bosutinib antitumor activity in colorectal cancer.
PMID: 19123474

Rich66 · 06-06-2009, 07:06 PM

Bosutinib is in trials for breast cancer by Wyeth, makers of Neratinib:
http://www.wyeth.com/irj/servlet/prt...its_253662.pdf

Rich66 · 10-03-2009, 03:48 PM

1: Mol Cell Endocrinol. 2009 Sep 20. [Epub ahead of print] Links: Valproic acid restores ERalpha and antiestrogen sensitivity to ERalpha-negative breast cancer cells.

Fortunati N, Bertino S, Costantino L, De Bortoli M, Compagnone A, Bandino A, Catalano MG, Boccuzzi G.
Oncological Endocrinology, AUO San Giovanni Battista, Torino, Italy.
Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ERalpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ERalpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ERalpha mRNA and protein, while did not modify ERbeta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ERalpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.
PMID: 19772891 [PubMed - as supplied by publisher