Valproic acid against er+ cancer (from top 5 list)

[Rich66]

1: Cancer Lett. 2008 Feb 8;259(2):156-64. Epub 2007 Nov 19. Links

Valproic acid is a selective antiproliferative agent in estrogen-sensitive breast cancer cells.

Fortunati N, Bertino S, Costantino L, Bosco O, Vercellinatto I, Catalano MG, Boccuzzi G.
Oncological Endocrinology, ASO San Giovanni Battista, Via Genova 3, 10126 Turin, Italy.
Treatment efficacy of breast cancer can be impaired by cell resistance. The aim of the study was to investigate the anti-tumour effects of valproic acid (VPA), the only clinically available histone deacetylase inhibitor, on both estrogen-sensitive and -insensitive breast cancer cells. VPA, at a concentration lacking severe adverse effects in human, reduces cell viability in estrogen-sensitive cell lines, inducing p21 expression and impairing cell cycle. In ZR-75-1, cell cycle is selectively arrested in G1, whereas MCF-7 cells massively accumulated in sub-G1. Actually, in MCF-7 cells, VPA induces apoptosis, down-regulates Bcl-2 and up-regulates Bak expression. In conclusion, VPA is a powerful antiproliferative agent in estrogen-sensitive breast cancer cells, making this drug of clinical interest as a new approach to treat breast cancer.
PMID: 18006146 [PubMed - indexed for MEDLINE

[Rich66]

Int J Biochem Cell Biol. 2009;41(1):225-34. Epub 2008 Aug 22. Links

Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status.

Travaglini L, Vian L, Billi M, Grignani F, Nervi C.
Department of Histology & Medical Embryology, University of Rome "La Sapienza", Italy; San Raffaele Bio-medical Park Foundation, Rome, Italy.
Estrogen receptors (ERs) are a recognized prognostic factor and therapeutic target in breast cancer. The loss of ER expression relates to poor prognosis, poor clinical outcome and impairs the use of anti-estrogenic treatment. Histone deacetylase inhibitors are candidate drugs for cancer therapy. Among them, valproic acid (VPA) is a long used and safe anti-epileptic drug. We studied the biological consequences of the chromatin remodeling action of VPA in a normal human mammary epithelial cell line and in ERalpha-positive and ERalpha-negative breast cancer cell lines. In these cells and regardless of their ER status, VPA-induced cell differentiation, as shown by increased milk lipids production, decreased expression of the CD44 antigen and growth arrest in the G(0)-G(1) phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21(WAF1/CIP1) gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G(2). ERalpha expression decreased in ERalpha-positive, increased in ERalpha-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERalpha target. VPA decreased the expression of the invasiveness marker pS2 in ERalpha-positive breast cancer cells, but did not cause its re-expression in ERalpha-negative cells. Overall, these data suggest that in both ERalpha-positive and -negative malignant mammary epithelial cells VPA reprograms the cells to a more differentiated and "physiologic" phenotype that may improve the sensitivity to endocrine therapy and/or chemotherapy in breast cancer patients.

[Rich66]

Clin Ther. 2008 Aug;30(8):1385-407. Links

Drug interactions between chemotherapeutic regimens and antiepileptics.

Yap KY, Chui WK, Chan A.
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
BACKGROUND: Drug-drug interactions (DDIs) are commonly seen in daily clinical practice, particularly in the treatment of patients with cancer. Seizures are often seen in patients with brain tumors and brain metastases, in whom antiepileptic drugs (AEDs) are often indicated. The risk for DDIs between anticancer drugs and AEDs is high. OBJECTIVE: This review aimed to investigate the types of interactions that are observed between the AEDs and the most commonly prescribed chemotherapeutic regimens. The risk for DDIs is discussed with regard to tumor type. METHODS: Data on DDIs between anticancer drugs and AEDs were compiled from the British National Formulary, Drug Information Handbook, and Micromedex Healthcare Series version 5.1. Product information of the individual drugs, as well as literature on anticancer drug-AED interactions, was searched using PubMed (years: December 1970 to January 2008; search terms: anticancer, antiepileptic, chemotherapy regimen, drug interactions, and the generic names of the individual anticancer drugs and AEDs [acetazolamide, carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide]). RESULTS: Our search identified clinically important DDIs observed with single-agent and combination regimens used for the treatment of breast cancers, colorectal cancers, lung cancers, lymphomas, and renal cell carcinomas. Carbamazepine, phenytoin, phenobarbital, and primidone were found to have prominent cytochrome P450 (CYP) enzyme-induction effects, while valproic acid had an inhibitory effect. The isozymes of major relevance to anticancer drug-AED interactions included CYP3A4, CYP2C9, and CYP2C19. Induction or inhibition of these isozymes by AEDs can cause a decrease or increase in anticancer drug concentrations. Similarly, enzyme inhibition or induction by anticancer drugs can lead to toxicity or loss of seizure control. CONCLUSIONS: In this review of anticancer drug-AED DDIs, carbamazepine, phenytoin, phenobarbital, primidone, and valproic acid were found to interact the most frequently with anticancer drugs. Based on the results of this review, clinicians should be vigilant when AEDs are prescribed concurrently with anticancer drugs. DDIs can be avoided or minimized by selecting alternative AEDs that are less likely to interact. However, if potentially interacting drug combinations must be used for treatment, serum drug concentrations should be closely monitored to avoid toxicity in the patient, as well as to ensure adequate chemotherapeutic and antiepileptic coverage.

[Rich66]

Eur J Pharmacol. 2007 Mar 29;560(1):17-22. Epub 2007 Jan 23. Links

Human melatonin MT1 receptor induction by valproic acid and its effects in combination with melatonin on MCF-7 breast cancer cell proliferation.

Jawed S, Kim B, Ottenhof T, Brown GM, Werstiuk ES, Niles LP.
Department of Psychiatry and Behavioural Neurosciences, McMaster University, HSC-4N77, 1200 Main Street West, Hamilton, Canada ON L8N 3Z5.
We have reported that valproic acid upregulates melatonin MT1 receptor expression in rat C6 glioma cells. In addition to its anticonvulsant and mood stabilizing properties, valproic acid can also inhibit the growth of cancer cells. Since the melatonin MT1 receptor has been implicated in the oncostatic action of melatonin on human MCF-7 breast cancer cells, the effect of valproic acid on its expression was examined in this cell line. Treatment of MCF-7 cells with valproic acid (0.5 or 1 mM) for 24 or 72 h caused a significant increase in melatonin MT1 receptor mRNA or protein expression, as shown by reverse transcription-polymerase chain reaction (RT-PCR) analysis and western blotting, respectively. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays revealed a concentration-dependent inhibition of MCF-7 cell proliferation by valproic acid (0.5, 1.0 or 5 mM), but melatonin (1 or 10 nM) was ineffective alone or in combination with valproic acid, in the first (MCF-7A) subline examined. However, in subsequent experiments using a different (MCF-7B) subline, which expressed higher levels of MT1 receptor mRNA and showed modest sensitivity to melatonin, a combination of this hormone with valproic acid produced a significant synergistic inhibition of cell proliferation. These findings indicate that clinically relevant concentrations of valproic acid upregulate melatonin MT1 receptor expression in human breast cancer cells. Moreover, the enhanced antiproliferative effect observed with a combination of valproic acid and melatonin suggests that a similar therapeutic approach may be beneficial in breast cancer.

[donocco5w4]

I have been interested in the Histone deacetylase action of Valproic Acid for years. This action of Vaproic acid is rarely mentioned in my pharmacy textbooks and as the drug penetrates the blood brain barrier well Im curious if it were used to treat the neuropathies of drugs such as Taxol as Neurontin (another antisiezure drug) is, whether it could help prevent or delay brain metastasis. Getting past the blood brain barrier is a big problem in oncologic therapy, and only as few drugs such as the various nitosureas ( Carmustine etc) and Temodar ( a different chemical class) penetrate the blood brain barrier well.

As mentioned in a previous post, one possiblem problem is the possibility of drug interactions. Valproic Acid can inhibit the metabolism of some drugs (with the anti-siezure drug lamictal this can be very dangerous) while Neurontin is eliminated unchanged by the kidney and doesnt cause drug interactions.

Paul

Paul