bms-387032 and Breast-Neoplasms

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure-activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Cycle; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinases; Female; Humans; Pharmaceutical Preparations; Protein Kinase Inhibitors

Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in many types of cancer cells by inhibiting Cdk7 and Cdk9, which control transcription. SNS-032 is a potent and selective inhibitor of Cdk2, Cdk7 and Cdk9 and has emerged in clinical trials. Here, we examined the viability of MCF-7 and MDA-MB-435 breast cancer cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways in breast cancer cells as shown by a dose-dependent increase in Annexin V-positive cells and terminal deoxynucleotidyl transferase-mediated dUTP nick?end labeling (TUNEL)-positive cells, as well as activation of caspase-8, -9 and poly(ADP-ribose) polymerase (PARP). At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and blocked RNA synthesis. Consistent with the inherently rapid turnover rates of their transcripts and proteins, the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) were rapidly reduced on exposure to SNS-032. Our results also indicated that SNS-032 suppressed the growth of breast cancer xenografts in mice. These data demonstrate that the use of SNS-032 may be a rational and novel therapeutic strategy for human breast cancer and warrants further clinical investigation.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 2; Female; Heterografts; Humans; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Oxazoles; Real-Time Polymerase Chain Reaction; Thiazoles; X-Linked Inhibitor of Apoptosis Protein

E2F1 and E2F4 are known to have opposing roles in cell cycle control. In the present work, we examine the role of both E2F1 and E2F4 in apoptosis induced by three cyclin-dependent kinase inhibitors (roscovitine, BMS-387032, and flavopiridol) as well as by three established chemotherapeutic drugs (VP16, cisplatin and paclitaxel). We find that E2F4 levels are diminished following treatment with cyclin dependent kinase inhibitors (flavopiridol, roscovitine and BMS-387032) or with DNA damaging drugs (cisplatin and VP16). In contrast, each of these drugs induced E2F1. We find that mouse fibroblasts nullizygous for the E2F4 gene are more sensitive to apoptosis induced by roscovitine, flavopiridol, cisplatin, and VP16, whereas E2F1-deficient fibroblasts are less sensitive. Likewise, we find that RNAi-mediated reductions in E2F4 in human cancer cells results in increased drug sensitivity. Taken together, these results support a model in which E2F1 and E2F4 play opposing roles during drug-induced apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; E2F4 Transcription Factor; Fibroblasts; Flavonoids; Humans; Lung Neoplasms; Mice; Mice, Knockout; Oxazoles; Piperidines; Protein Kinase Inhibitors; Purines; RNA, Small Interfering; Roscovitine; Thiazoles; Transcription Factors; Tumor Cells, Cultured