Perspectives on natural product epigenetic modulators in chemical biology and medicine

Epigenetic therapies from natural products in the clinic

1. Clinically approved natural product epigenetic modulators

Despite an increasing number of synthetically-derived epigenetic modulators being taken into preclinical and clinical studies, only a very limited set of natural product agents has reached the clinic in this field. Two have been approved by the food and drug administration (FDA) for commercialisation: azacitidine, a DNMT inhibitor, and romidepsin, an HDAC inhibitor.

2. Azacitidine

The nucleoside analogue azacitidine (5-azacytidine, 5-AC) was investigated from as early as the 1960s as a chemotherapeutic treatment of acute myelogenous leukemia (AML). Although 5-AC was originally discovered from a series of synthetic nucleoside analogues, it was later found to also be a natural product, produced by the bacterium Streptoverticillium ladakanus. Mechanistically, it was subsequently found that 5-AC and its related analogue 5-aza-2’-deoxycytidine, once incorporated into DNA, could inhibit DNA methylation through irreversible inhibition of DNMT enzymes. This leads to DNMT depletion during cell division, driving DNA hypomethylation. Such changes in the DNA methylation state were linked to the reactivation of aberrantly silenced genes, demonstrating the use of these nucleoside analogues as therapeutics and as tool molecules to understand the effects of silenced regulatory genes. Currently 5-AC has FDA approval for the treatment of myelodysplastic syndrome (MDS), a haemato-logical condition that has poor prognosis for progression into AML if untreated. Unfortunately, while 5-AC is efficacious in the clinic for haematologic malignancies, its activity against solid tumours has been poor and oen accompanied by significant side effects at the doses required for efficacy.

3. Romidepsin

In 2009 the bicyclic depsipeptide romidepsin, isolated from Chromobacterium violaceum, was approved for intravenous infusion as an anticancer agent (Istodax) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is a pro-drug, the disulfide bond being reduced in cells to yield the corresponding dithiol as the active molecule. It is a potent class I HDAC inhibitor agent, with a good selectivity over class IIHDACs. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of several cancer cell lines. In vivo studies have also demonstrated cytotoxic activity in xenografts of A549 and MCF-7 cancer cell lines. Romidepsin is currently undergoing a large number of clinical trials for the prevention and treatment of a variety of cancer types, either as a monotherapy or in combination with other agents. As highlighted earlier, the synergistic effects of combinations of epigenetic modulators may prove particularly important to mediate a given epigenetic response. Indeed, a combination of romidepsin and azacitidine (DNMT inhibitor, see above), is being studied in order to determine their efficacy in the treatment of advanced solid tumors.

4. Other natural products under clinical investigation reported to impact epigenetic mechanisms

Ursodeoxycholic acid, is a secondary bile acid used in the treatment of a certain liver diseases, and it has been reported in preclinical studies to show potential in colon cancer prevention. The precise mechanism(s) of the chemopreventive effect induced by UDCA is unknown. Recently, it has been reported that UDCA induces differentiation and senescence bymodulating histone acetylation. UDCA has been shown to induce hypoacetylation of histones, albeit in vitro. Further investigation in HCT116 cells, using microarray screening and RT-PCR, revealed that ursodeoxycholic acid is able to up-regulate expression of HDAC6, which may mediate the reported effects. In 2003, UDCA underwent a randomized phase II clinical trial in comparison to acetylsalicylic acid and sulindac for its activity in preventing colorectal cancer.

Several polyphenolic compounds are currently undergoing clinical trials as preventive or therapeutic agents.One of themost studied is the yellow pigment curcumin, which is themajor active component of the spice turmeric(Curcuma longa). Curcumin has been reported to have potent cancer chemopreventive effects and to be very well tolerated, even at high doses. Nonetheless, curcumin has been shown to hit a large number of molecular targets, including several epigenetic pathways. Indeed, curcumin has been found to inhibitHATs77 and DNMTs, and to deregulate the expression of several miRNAs in BxPC-3 human pancreatic cancer cell line. Whether the activity of this compound on such epigenetic targets is responsible for its efficacy remains to be rigorously established. Currently curcumin is being evaluated in several clinicaltrials for the prevention or treatment of a number of diseases. For example, curcumin is undergoing a phase II clinical trial for its effects on age-related cognitive impairment.



Fanny L. Cherblanc, Robert W. M. Davidson, Paolo Di Fruscia, Nitipol Srimongkolpithak, Matthew J. Fuchter*. Nat. Prod. Rep., 2013, 30, 605–624


Related Products

CAS Number Product Name Molecular Weight Molecular Formula Description
128517-07-7 Romidepsin 540.7 C24H36N4O6S2 Romidepsin strongly inhibits HDAC1 and HDAC2 with IC50 of 1.6 nM and 3.9 nM, respectively, but is relatively weak in inhibiting HDAC4 and HDAC6 with IC50 25 nM and 790 nM, respectively.