piperidines and perifosine

The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Phosphorylcholine; Piperidines; Proteasome Inhibitors; Pyridines; Remission Induction; Thalidomide; Thiazoles; Treatment Outcome; Vorinostat

Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression.

Topics: Aminopyridines; Animals; Benzimidazoles; CHO Cells; Cricetinae; Cricetulus; Hep G2 Cells; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Phosphorylcholine; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Receptors, LDL; Ribonucleosides; RNA Stability; RNA, Messenger; Transcriptional Activation

The ether phospholipid AMG-PC (1-O-hexadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-16-OCH3) affects rat mast cell responses in a dual manner. A powerful synergistic interaction with the ionophore A23187 and the phorbol ester TPA indicated an involvement of mechanisms relating to activation of protein kinase C. In contrast, the related hexadecylphosphocholine (miltefosine) only causes inhibition. Here, the investigation is extended to include the antineoplastic ether phospholipids ET-18-OCH3 (edelfosine) and BM 41.440 (ilmofosine) as well as the heterocyclic hexadecylphosphocholine analogues D-20133 and D-21266. The four test drugs had an influence very similar to that of AMG-PC on mast cell responses to selected secretagogues, i.e., they both enhanced and inhibited antigen-induced histamine release whereas only inhibition was observed with compound 48/80. They significantly amplified the response to A23187 alone as well as in combination with TPA and, under certain conditions, inhibitory effects were observed with ET-18-OCH3, D-20133 and D-21266 but not with BM 41.440. The latter was more effective in enhancing A23187 mediated responses and had a wider concentration range of activity than the other three drugs. D-20133 and D-21266 influenced mast cells in a manner distinct from that of hexadecylphosphocholine and may share cellular targets with the ether phospholipids. The results raise speculation of an involvement of mast cells in the immunomodulatory action of these drugs.

Topics: Animals; Antineoplastic Agents; Calcimycin; Histamine Release; Ionophores; Male; Mast Cells; Phorbol Esters; Phospholipid Ethers; Phosphorylcholine; Piperidines; Rats; Rats, Wistar