Ibulocydine Is a Novel Prodrug Cdk Inhibitor That Effectively Induces Apoptosis in Hepatocellular Carcinoma Cells

Abstract

Hepatocellular carcinoma (HCC)3 is a leading cause of mortality in patients with liver cirrhosis (1). In the United States, the incidence of HCC has risen during the last few decades from 1.3/100,000 population between 1978 and 1980 to 3.3/100,000 population between 1998 and 2001 (2, 3). This is likely to continue, primarily due to progressive liver diseases attributable to the hepatitis C virus in individuals infected a few decades ago (4). However, as hepatitis B virus infection is more prevalent globally than hepatitis C virus, hepatitis B virus remains the single most important cause of HCC worldwide, and is particularly high in Asia and Africa (5). Treatment of HCC is clinically difficult, as HCC expresses multidrug-resistance genes and is insensitive to current chemotherapeutic agents (6). HCC cells are characterized by high cellular levels of cyclin-dependent kinases (Cdks). Up-regulation of Cdks results from the inactivation of p16 Ink4, p21Waf1 and p27 Kip1 , Cdk inhibitory proteins, and abnormal activation of cyclins (7-10). For this reason, Cdk inhibitors are strong candidates for the treatment of HCC, and some (e.g. olomoucine, roscovitine and flavopiridol) have been tested in clinical trials (11).Cdks regulate two biological processes essential for cancer cell survival: cell cycle progression and gene transcription (12). They control entry into each stage of the cell cycle by phosphorylating key substrates such as pRb (13,14). Cdks usually form heterodimers with cyclins to create active complexes and, because cyclin levels oscillate throughout the cell cycle, this contributes to the temporal activation of specific Cdks. Cdks also regulate transcription by phosphorylating the carboxylterminal domain (CTD) of the large subunit of RNA polymerase II (15). In humans, the CTD contains 52 heptapeptide (YSPTSPS) repeats that can be phosphorylated on serines, threonines, and tyrosines (15). A number of Cdks phosphorylate these sites, including Cdk7/cyclin H/Mat1 (part of the TFIIH complex that initiates transcription) (16) and Cdk9/cyclin T (also called P-TEFb), which activates transcriptional elongation (17-21).Mcl-1, an anti-apoptotic member of the Bcl-2 family (22), was first identified as a protein up-regulated in a human carcinoma cell line induced to differentiate along the monocyte lineage (23), and is essential for the survival of carcinoma cells (24 -27). Mcl-1 is thought to act by antagonizing pro-apoptotic proteins such as Bim (28). Inhibitor of apoptosis protein (IAP) is a family of proteins that regulates cell death; X-linked IAP (XIAP) and survivin are two important members of this family in mammals. Both inhibit caspases and block apoptosis (29).Ibulocydine, ((2S,3S,4S,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo [2,3-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate, is an isobutyrate ester prodrug of a novel synthetic Cdk inhibitor, BMK-Y101 (4-amino-6-bromo-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidine-5-carboxamide) ...

Raman spectroscopic study of 6-amino-7-deazapurine

“…A compound of deazapurines as a purine-based metabolite has diverse functions ranging from secondary metabolism to RNA modification [11]. 6-Amino-7-deazapurine (6A-7DAP)-consisting nucleosides have been identified as a novel inhibitor of cyclin-dependent kinases (CDKs) [12]. Unlike the adenine purine unit, this 6A-7DAP ring does not have a nitrogen atom in its N7 position, whereas the pentose ring attaches to the N1 atom of the CDK compounds.…”

Ibulocydine sensitizes human cancers to radiotherapy by induction of mitochondria-mediated apoptosis

“…We previously reported that IB, a novel inhibitor of Cdk7/9, caused rapid downregulation of anti-apoptotic proteins, thus inducing apoptosis in human hepatocellular carcinoma cells [8]. SNS-032 has been also reported by Chen et al [13] as an inhibitor of Cdk2/7/9 that decreased the mRNA and protein levels of antiapoptotic protein in chronic lymphocytic leukemia.…”

“…Ibulocydine (IB) is an isobutyrate ester prodrug of a novel synthetic Cdk inhibitor and has activity against Cdk7 and Cdk9. IB displayed antiproliferative and antitumoral effects in human hepatocellular carcinoma cells as in our previous report [8]. IB caused rapid downregulation of anti-apoptotic protein, thus inducing apoptosis.…”

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

“…Ibulocydine, a novel prodrug inhibitor of CDK7/9, effectively inhibits the growth of HCC with significant reduction in the phosphorylation of RNAPII at Ser‐5 and Ser‐2 in dose‐ and time‐dependent manners . As a covalent inhibitor of CDK7, THZ1 shows potent antiproliferative activity on several cancers .…”