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To the editor,
The recent article by Chen et al. [1] provided for highly stimulating reading. Valproic acid mitigates tumor growth in a number of systemic malignancies besides gliomas.
Similar effects are seen in prostate carcinomas. Valproic acid causes augmentation of p27 levels leading to cell cycle arrest in the cancerous cells [2]. The expression of androgen receptors by the malignant tumor is also decreased. At the same time E-cadherin expression is augmented markedly [3]. Angiogenesis is also inhibited at the same time thus decreasing tumor growth. Cyclin D1 expression is also attenuated at the same time, while cytokeratin-18 expression is increased [4]. This results in a decrease in tumor invasiveness as well as a decline in cancer cell migration. Valproic acid also has an augmenting effect on the radio-sensitivity of prostate carcinomas [5]. It mediates this effect via acetylated p53 dependent modulation of mitochondrial membrane potential in the cancerous cells. Similar effects have been seen in bladder carcinomas. It mediates its anti-neoplastic effect in bladder tumors by inhibiting histone deacetylase [6]. Simultaneous up-regulation of thrombospondin-1 expression is also seen in bladder carcinomas.
Similarly, valproic acid inhibits tumor growth in colo-rectal malignancies. These effects are especially seen when it is used in combination with IIF. The dual combination enhances Bax expression while Bcl-2 expression is markedly reduced [7]. TIMP-1 activity is also enhanced at the same time, while MMP2 activity is considerably reduced. These effects are time dependent. The combination also markedly up-regulates the expression of RXRγ. Histone deacetylase activity is also markedly reduced. Valproic acid also augments the radio-sensitivity of colon carcinomas. p53 plays a major role in this valproic acid mediated radio-sensitization. It is clear from the above examples that valproic acid may have significant tumor attenuating effects. There is an urgent need to fully as well as further evaluate these anti-neoplastic effects.
References
Chen Y, Tsai Y-H, Tseng S-H (2012) Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms. J Neurooncol 109:23–33
Sidana A, Wang M, Shabbeer S et al (2012) Mechanism of growth inhibition of prostate cancer xenografts by valproic Acid. J Biomed Biotechnol 2012:180363
Zhang L, Wang G, Wang L, Song C, Wang X, Kang J (2011) Valproic acid inhibits prostate cancer cell migration by up-regulating E-cadherin expression. Pharmazie 66:614–618
Chen X, Wong JY, Wong P, Radany EH (2011) Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis. Mol Cancer Res 9:448–461
Byler TK, Leocadio D, Shapiro O et al (2012) Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression. BMC Urol 12:21
Papi A, Ferreri AM, Guerra F, Orlandi M (2012) Anti-invasive effects and proapoptotic activity induction by the rexinoid IIF and valproic acid in combination on colon cancer cell lines. Anticancer Res 32:2855–2862
Chen X, Wong P, Radany E, Wong JY (2009) HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells. Cancer Biother Radiopharm 24:689–699
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Kapoor, S. Valproic acid and its inhibition of tumor growth in systemic malignancies: beyond gliomas. J Neurooncol 113, 531 (2013). https://doi.org/10.1007/s11060-013-1129-z
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DOI: https://doi.org/10.1007/s11060-013-1129-z