Romidepsin (FK228) and its analogs directly inhibit phosphatidylinositol 3‐kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3‐kinase dual inhibitors

Abstract

Activation of phosphatidylinositol 3-kinase (PI3K) signaling is involved in carcinogenesis and cancer progression. The PI3K inhibitors are considered candidate drugs for cancer treatment. Here, we describe a drug screening system for novel PI3K inhibitors using Saccharomyces cerevisiae strains with deleterious mutations in the ATP-binding cassette transporter genes, because wild-type S. cerevisiae uses drug efflux pumps for reducing intracellular drug concentrations. By screening the chemical library of the Screening Committee of Anticancer Drugs, we identified the histone deacetylase (HDAC) inhibitor romidepsin (FK228) and its novel analogs. In vitro PI3K activity assays confirmed that these compounds directly inhibit PI3K activity at lM-range concentrations. FK-A5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of protein kinase B and downstream signaling components. Molecular modeling of the PI3K-FK228 complex indicated that FK228 binds to the ATP-binding pocket of PI3K. At lM-range concentrations, FK228 and FK-A5 show potent cytotoxicity, inducing apoptosis even in HDAC inhibitor-resistant cells. Furthermore, HDAC/ PI3K dual inhibition by FK228 and FK-A5 at lM-range concentrations potentiates the apoptosis induction, mimicking the effect of combining specific HDAC and PI3K inhibitors. In this study, we showed that FK228 and its analogs directly inhibit PI3K activity and induce apoptosis at lM-range concentrations, similar to HDAC/PI3K dual inhibition. In future, optimizing the potency of FK228 and its analogs against PI3K may contribute to the development of novel HDAC/PI3K dual inhibitors for cancer treatment. (Cancer Sci 2012; 103: 1994-2001 P hosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH group of the inositol ring, generating phosphatidylinositol 3,4,5-trisphosphate (PIP3).(1) In turn, PIP3 activates protein kinase B (AKT) and downstream molecules, leading to increased cell growth, proliferation, and survival.(2) Class IA PI3K is composed of a catalytic subunit, p110, and a regulatory subunit, p85. PIK3CA encodes p110a, and is frequently mutated in human cancers.(3) Because almost all of the mutations are functionally active, (4) activation of PI3K is likely to play a crucial role in carcinogenesis and cancer progression. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates PIP3 to PIP2 as the catalytic counterpart of PI3K.(5) In addition to PIK3CA mutations, inactivating mutations in, or loss of, PTEN have also been observed in human cancers, supporting the involvement of PI3K in cancer. (6) Therefore, inhibitors of PI3K are considered to be candidate drugs for cancer therapy. Indeed, some PI3K inhibitors have entered clinical trials, but efforts are still underway to develop new PI3K inhibitors. To discover novel PI3K inhibitors, we took advantage of a drug screening system that uses a strain of the yeast Saccharomyces cerevisiae with deleterious mutatio...

Protein Kinase and HDAC Inhibitors from the Endophytic Fungus Epicoccum nigrum

“…It was previously reported that the HDAC inhibitor romidepsin (FK228) and its analogues inhibit phosphatidylinositol 3 kinase activity leading to increased effects on cancer cell death. 41 Furthermore, several kinases inhibited by these compounds interact with proteins either associated with histone acetylation or deacetylation or with regulators of this activity ( Figure 5). Indeed, SRC and AKT interact directly with HDAC3, while PRK1 interacts with both HDAC5 and HDAC6.…”

Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms

“…Third, the drugs could have additional offtarget effects. For instance, romidepsin has been reported to inhibit PI3K signaling (42). In fact, some differences between the effects of romidepsin and givinostat on UCCs could be explained by off-target activities.…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…CUDC-907 is another dual-acting agent developed by the same research group to inhibit both HDACs and phosphoinositide 3-kinase (PI3K) (Qian et al 2012) and its clinical trials are underway for the treatment of lymphoma and multiple myeloma as well as advanced/relapsed solid tumors. Romidepsin (FK228, depsipeptide) is a potent Class I histone deacetylase inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas, and recent research demonstrated that FK228 and its analogs (FK-A5 and FK-A11) act as HDACs and PI3K dual inhibitors (Saijo et al 2012; Saijo et al 2015). …”