Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.
http://plosone.org/article/info:doi/10.1371/journal.pone.0000098#article1.front1.article-meta1.abstract1.sec4.p1

Sometime around 2002 the concept that chromatin alterations such as DNA methylation and histone acetylation, was accepted in oncological literature and intents to reactivate tumor-suppressors were initiated (1), in spite that the mechanism of anticancer epigenetic drugs work, were and are still unclear. Furthermore, it was evident that in some cases, these epigenetic therapies administered concomitantly with cytotoxics seems to add short-term therapeutic benefits with relatively low toxicity.

On the first hand, the precise combination among hydralazyne (an demethylating agent) plus valproic acid (deacetylase inhibitor) has been supported by several researcher groups. Arce et al. showed interest in pursuing this drugs combination in cancer therapy from the first article published in this journal (2) to the last publication in December 2011 (3), at the best of my knowledge. This situation is important because the wide experience that they have acquired (7 or more articles from the same group, according to a rapid search in PubMed with the words: valproic acid, hydralazine, and cancer ), in anticancer research with the use of these medications, disclosing positive results both in vitro and in vivo studies.

On the other hand, the dark-side of the demethylating agents / deacetylase inhibitors has been extensively reported; nowadays knowledge about adverse effects is well known (4, 5, 6, 7, 8). So, we can say that the positive effects of epigenetic therapy appear side by side with the negative ones. It is possible that final result of epigenetic therapy can be context dependent albeit we do not know yet which patients will enjoy positive effects or vice versa. Although in 2007, I sent to Plos One a published commentary (9) regarding the dangers of administering this type of therapy before we can gather more data about safety (8), Duenas (from the group of Arce et al.) replied that “… it is not unexpected that epigenetic drugs may activate (at transcriptional level) .. pathways with antiapoptotic actions. However, the overall effect (he continues) may still be growth inhibitory upon tumors (8) …”

The reason of this new comment is that I have received in my office a patient with cholestatic jaundice but without evidence of organic hepatic disease. Under the suspiciousness of having a rare paraneoplastic syndrome, I decided to send her to an oncologist, who found a small renal malignant mass. Taking advantage of the ample experience that Dueñas et al have collected during its extensive work administering hydralazine/valproic in oncologic patients and because my patient had been under valproic acid therapy for her epilepsy, I am asking if this "Janus effects" of epigenetic therapy, that upregulates & downregulates so many genes, can be responsible. In this road, Cruz-Hernandez (belonging to the same group) reported (4): “...Treatment for seven days with hydralazine and valproate … 10,226 genes … underwent 2-fold over or underexpression … … A number of these … genes have a definitive role as a tumor suppressors (4, emphasis was added by me)…”.

Naturally, we are compelled to ask how we can use this observation to our patient’s advantage. We definitively know now that in the epigenetic treatment of clear Renal Cell tumors with the demethylating agent or an histone deacetylase inhibitor, given alone or together, can increase significantly the expression of human edogenous retrovirus (H-ERVs)(7), causing a number of circulating related antigens, that can be the source of paraneoplastic expression (besides the opportunity to develop monoclonal antibodies for immunotherapy, like actually occurs with Rheumatoid Arthritis (10) currently). In short, have Dueñas et al, knowledge about any paraneoplastic increment during the follow-up of their patients during this long saga of more than 6 years studying the anticancer effects with these drugs?

Moreover and possibly most important, molecular toxicity with demethylating and/or deacetylase inhibitor agents, by disrupting the function of a tumor-suppressor, (discovered in renal clear cell malignancies) provokes the upregulation of H-ERVs , which in turn induced the activation of HIF-mediated hypoxia- pathways even during normoxia (7). Being this the case, it can be expect that if this therapy (valproic acid) continues in a patient, the course of any malignant disease that they may have, can be more accelerated than if we can change the antiepileptic program. Importantly, the same situation has been described in Breast Cancer patients (10). Under these circumstances, Dueñas et al. may have noticed accelerated progression of malignant growth after the initial benefits of the epigenetic therapy have been stabilized. Do this events have taken place? Of course, these unfortunate outcomes will be detected with analyzing the confounding factors that represents the natural evolution of the breast malignancy and correlating it with HERVs increment, situation that needs to be searched for. Alternatively, detection of HIF-1-alpha or HIF-2-alpha in the malignant tissues will also represent a poor prognosis. Hence, a carefully follow-up in patients treated with valproic acid or hydralazine drugs is mandatory.

In brief, I would appreciate comments regarding the follow up of the breast cancer patients that have received therapy with these drugs, to learn about quantitative HERVs increments or the HIF-1/2-alpha pathway activation in the breast patients treated by Duenas et al. group, expecting acquire expertise that we can use in our patient’s advantage.

Bibliography:

1. Brown R, Strathdee G. Epigenomics and epigenetic therapy of cancer. Trends Mol Med. 2002;8:Suppl 4:43-8.

2. Arce C, Pérez-Plasencia C, González-Fierro A, de la Cruz-Hernández E, Revilla-Vázquez A, et al. (2006) A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer. PLoS ONE 1(1): e98.

3. Chávez-Blanco A, De la Cruz-Hernández E, Domínguez GI, Rodríguez-Cortez O, Alatorre B, Pérez-Cárdenas E, Chacón-Salinas R, Trejo-Becerril C, Taja-Chayeb L, Trujillo JE, Contreras-Paredes A, Dueñas-González A. Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate. Int J Oncol. 2011 Dec;39(6):1491-9.

4. De la Cruz-Hernández E, Perez-Plasencia C, Pérez-Cardenas E, Gonzalez-Fierro A, Trejo-Becerril C, Chávez-Blanco A, Taja-Chayeb L, Vidal S, Gutiérrez O, Dominguez GI, Trujillo JE, Duenas-González A. Transcriptional changes induced by epigenetic therapy with hydralazine and magnesium valproate in cervical carcinoma. Oncol Rep. 2011 Feb;25(2):399-407.

5. Saito M, Suzuki K, Maeda T, Kato T, Kamiyama H, Koizumi K, Miyaki Y, Okada S, Kiyozaki H, Konishi F. The accumulation of DNA demethylation in Sat α in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals. Oncol Rep. 2012 Jun;27(6):1717-25.

6. Van Tine BA, Kappes JC, Banerjee NS, Knops J, Lai L, Steenbergen RD, Meijer CL, Snijders PJ, Chatis P, Broker TR, Moen PT Jr, Chow LT.
Clonal selection for transcriptionally active viral oncogenes during progression to cancer. J Virol. 2004 Oct;78(20):11172-86.

7. Pazolli E, Alspach E, Milczarek A, Prior J, Piwnica-Worms D, Stewart SA. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res. 2012 May 1;72(9):2251-61.

8. Cherkasova E, Malinzak E, Rao S, Takahashi Y, Senchenko VN, Kudryavtseva AV, Nickerson ML, Merino M, Hong JA, Schrump DS, Srinivasan R, Linehan WM, Tian X, Lerman MI, Childs RW. Inactivation of the von Hippel-Lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene. 2011 Nov 24;30(47):4697-706.

9. Duenas replied to svalemayorga on 29 Jan 2007 at 14:35 GMT. RE: Valproate may induce PI3K/Akt pro-tumorigenic pathway. Commnetary regarding: A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer. PLoS ONE 1(1): e98.

10. Wang-Johanning F, Rycaj K, Plummer JB, Li M, Yin B, Frerich K, Garza JG, Shen J, Lin K, Yan P, Glynn SA, Dorsey TH, Hunt KK, Ambs S, Johanning GL.
Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J Natl Cancer Inst. 2012 Feb 8;104(3):189-210.