ABSTRACT
Shedding light on the matter: Rhenium(I) indolato complexes with highly potent visible-light-triggered antiproliferative activity (complex 1: EC50 light=0.1 µM vs EC50 dark=100 µM) in 2D- and 3D-organized cancer cells are reported and can be traced back to an efficient generation of singlet oxygen, causing rapid morphological changes and an induction of apoptosis.
Subject(s)
Antineoplastic Agents/pharmacology , Light , Organometallic Compounds/pharmacology , Rhenium/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
Inhibitors of protein deacetylases represent a novel therapeutic option for cancer diseases due to their effects on transcriptional regulation by interfering with histones acetylation and on several other cellular pathways. Recently, their ability to modulate several transcription factors and, interestingly, also co-factors, which actively participate in formation and modulation of transcription complexes was shown. We here investigate whether HMGA2 (High Mobility Group AT-2 hook), a nuclear non-histone transcriptional co-factor with known oncogenic properties, can be influenced by the novel pan-deacetylase inhibitor panobinostat (LBH589) in human hepatocellular carcinoma models. Panobinostat strongly downregulated HMGA2 in HepG2 and Hep3B cells; this effect was mediated by transcriptional upregulation and promotion of the maturation of the tumorsuppressor miRNA hsa-let-7b, which could inhibit HMGA2 expression via RNA interference pathways. siRNA knockdown of HMGA2 or transfection of hsa-let-7b mimicking oligonucleotides confirmed the role of HMGA2 in regulating cell proliferation and apoptosis in liver cancer cell lines. Co-incubation with panobinostat showed an additive effect on inhibition of cell proliferation using an impedance-based real-time cell analyzer. Treatment of HepG2 xenografts with panobinostat also led to a downregulation of HMGA2 in vivo. These findings show that pan-deacetylase inhibitors also modulate other signaling pathways and networks than histone modifications to influence cell fate.
Subject(s)
Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , HMGA2 Protein/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Antineoplastic Agents/pharmacology , Base Sequence , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Down-Regulation/drug effects , Gene Knockdown Techniques , HMGA2 Protein/genetics , HMGA2 Protein/metabolism , Hep G2 Cells , Humans , Indoles , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Models, Biological , Panobinostat , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , RNA, Small Interfering/genetics , Signal Transduction/drug effects , Transplantation, HeterologousABSTRACT
INTRODUCTION: Inhibition of protein kinases has become a standard of modern clinical oncology. PIM1 belongs to a novel class of serine/threonine kinases with distinct molecular and biochemical features regulating various oncogenic pathways, for example hypoxia response, cell cycle progression and apoptosis resistance. PIM1 is overexpressed in human cancer diseases and has been associated with metastasis and overall treatment response; in experimental models, inhibition of PIM1 suppressed cell proliferation and migration, induced apoptotic cell death and synergized with other chemotherapeutic agents. AREAS COVERED: A PubMed literature search was performed to review the currently available data on PIM1 expression, regulation and targets; its implication in different types of cancer and its impact on prognosis are described. We present ATP-competitive PIM1 inhibitors and the state of the art of PIM1 inhibitor design. Finally, we highlight the development of the unusual class of highly selective and potent organometallic PIM1 inhibitors. EXPERT OPINION: As PIM1 possesses oncogenic functions and is overexpressed in various kinds of cancer diseases, its inhibition provides a new option in cancer therapy. Based on the ability of highly selective organometallic PIM1 inhibitors, promising in vivo applicability is expected.
Subject(s)
Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Animals , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-pim-1/genetics , Proto-Oncogene Proteins c-pim-1/metabolismABSTRACT
A metal complex is identified in which the metal fulfills two independent functions: as a structural scaffold for the specific molecular recognition of protein kinases resulting in antiangiogenic properties, together with a visible-light-induced photoreactivity triggering apopotosis in cancer cells.
