Histone Deacetylase Inhibitors as Therapeutics for Endometriosis

Xin Li; Xishi Liu; Sun-Wei Guo

Disclosures

Expert Rev of Obstet Gynecol. 2012;7(5):451-466. 

In This Article

Possible Mechanisms of Action of HDACIs as a Therapeutic Agent

As alluded to earlier, quite extensive in vitro and in vivo studies have shown that certain HDACIs such as VPA and TSA can promote apoptosis, hinder cell cycle progression, inhibit proliferation, reduce inflammation and angiogenesis, reduce uterine hyperactivity, and attenuate invasiveness in endometriosis. In other cell types, VPA has been shown to reduce basal and FSH-stimulated estrodiol secretion and FSH-induced aromatase activity in human ovarian follicular cells[101] and in forskolin-stimulated H295R cells.[102] Thus, VPA may potentially interfere with steroidogenesis in endometriosis.

In human myometrial cells, it has been shown that long-term treatment with HDACIs resulted in repression of NF-κB DNA binding and inhibition of the expression of proinflammatory genes such as COX-2, IL-8, IL-6 and RANTES.[103] HDACIs have been reported to suppress TNF-α-induced tissue factor expression[104] and also suppress the transcription, expression and secretion of VEGF in endometriotic cells[69] and other cell types.[105] Both tissue factor and VEGF (and its receptors) are known to be key players involved in angiogenesis in endometriosis.[106–108] The authors' unpublished data also indicate that VPA can inhibit the expression of oxytocin receptor (OTR) in primary myometrial smooth muscle cells [Guo S-W et al., Unpublished data], where OTR is known to play a major role in uterine contractility in pregnant and non-pregnant uteri OTR expression has been found to be significantly and positively correlated with the amplitude of uterine contractility and also with the severity of dysmenorrhea in women with adenomyosis [Guo et al., Unpublished data]. Table 2 summarizes the various effects of HDACIs on the expression of some important genes that are known to be involved in endometriosis. Figure 1 depicts the possible mechanisms of action, explaining how HDACIs such as VPA can be therapeutically valuable.

Figure 1.

Schematic illustration of potential therapeutic effects of histone deacetylase inhibitors in endometriosis. HDACI: Histone deacetylase inhibitor. Modified from Figure 22.1 in [143].

HDACIs appear to energize with DMAs, resulting in a greater antiproliferative effect than either used alone and more robust re-expression of methylation-silenced genes,[24] as in cancer cells.[109] However, little data are available in the context of endometriosis, necessitating further research.

Treating Endometriosis With HDACIs: Pain or Infertility?

Based on the existing preclinical data and some clinical observations, it seems that HDACIs such as VPA may be suitable for treating patients with endometriosis complaining of dysmenorrhea or other endometriosis-related pain. Despite the potential of HDACIs in inducing differentiation of endometrial cells, it is unclear as of now about the potential of HDACIs in treating endometriosis-related infertility. This uncertainty may be compounded by the teratogenic effect of VPA. Thus, even for treating endometriosis-related pain, contraception procedures may still be needed. That said, one cannot rule out the potential to treat endometriosis-induced infertility just because it is teratogenic. In theory, endometriosis-induced infertility can still be treated with VPA and its teratogenic effects can be avoided.

The Unknowns: The Need for Future Studies

Despite extensive data, future studies should examine which HDACs are critically involved in the development of endometriosis, and what types of HDACIs, pan or specific, are better in terms of efficacy and side-effect profiles. Since there are at least three subtypes of endometriosis,[110] and different subtypes of endometriosis apparently have different gene-expression profiling patterns,[111] it is plausible that these subtypes may also have different epigenetic aberrations and thus require different therapeutic interventions. Even within the same subtype, it is still possible that, depending on the duration of endometriosis, patterns of gene dysregulation and thus epigenetic aberration may be different,[20] and, as such, may demand a different therapeutic approach. This is particularly true since most preclinical animal efficacy studies involve genetically and pathologically homogeneous animals with identical or nearly identical disease progression.

Histone acetyltransferases and HDACs can also modify nonhistone proteins. Unfortunately, few, if any, studies on this in the context of endometriosis have been published. It may be worthy of investigation in future studies.

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