ABSTRACT
Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.
Subject(s)
DNA Repair/genetics , Drug Resistance, Neoplasm/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Transcription, Genetic , Animals , Apoptosis/drug effects , Cell Line, Tumor , Clinical Trials as Topic , Dioxoles/therapeutic use , Drug Synergism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Mice , Tetrahydroisoquinolines/therapeutic use , Trabectedin , Tumor Cells, Cultured , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
Breast cancer is still the leading cause of cancer deaths among women worldwide, and new therapies to treat this dangerous disease are desperately needed. The serendipitously found anticancer drug cisplatin and its second-generation congener carboplatin appear to be promising drug systems for the treatment of breast tumors, in particular of multidrug resistant and highly aggressive triple-negative subtypes. In the wake of these platinum drugs, complexes of the coinage metals copper, silver, and gold were developed that showed enhanced selectivity for breast cancer while causing fewer and weaker side-effects. This review takes stock of the latest developments in the field of coinage metal anticancer drugs with an emphasis on their biological and mechanistic aspects. Pertinent literature is covered up to 2012.
Subject(s)
Breast Neoplasms/drug therapy , Coordination Complexes/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Female , Gold/chemistry , Humans , Silver/chemistryABSTRACT
An overview of anticancer active spirocyclopropanes of the illudin class is provided. After a short introduction on the history and general chemistry of illudins M and S, new discoveries concerning their mode of action and metabolism are reported as well as new synthetic endeavors towards derivatives with improved selectivity for and efficacy against cancer cells. In addition, common and recently tapped biological sources and isolation procedures for known and new illudins are discussed. Pertinent literature is covered up to 2010.
Subject(s)
Alkylating Agents/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery/methods , Spiro Compounds/pharmacology , Alkylating Agents/chemical synthesis , Alkylating Agents/chemistry , Alkylating Agents/isolation & purification , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Humans , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/isolation & purificationABSTRACT
Doxorubicin N-acylhydrazones derived from saturated, unsaturated and terpene-terminated fatty acids were tested for anticancer activity in cells of human HL-60 leukaemia, 518A2 melanoma, MCF-7/Topo breast and KB-V1/Vbl cervix carcinomas. In the latter, the N-heptadecanoyl hydrazone was more cytotoxic than its unsaturated C18-fatty acyl analogues and even three times more than doxorubicin. The (menthoxycarbonyl)undecanoyl hydrazone was twice as active as doxorubicin in these multidrug resistant KB-V1/Vbl and in the 518A2 cells and also more efficacious in KB-V1 and MCF-7 cells that had been desensitised for doxorubicin. All hydrazones induced apoptosis albeit by slightly different mechanisms. While apoptosis induction by the menthoxymalonyl hydrazone was characterized by an upfront increase in caspase-8 activity, all other hydrazones elicited a hike in caspase-9 activity. Treatment of HL-60 and 518A2 cells with doxorubicin or its heptadecanoyl, linolenoyl, (menthoxycarbonyl)undecanoyl or menthoxymalonyl hydrazones also led to diverging increases of the ratio of bax to bcl-2 mRNA expression, of reactive oxygen species and of mitochondrial membrane damage.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Fatty Acids/chemistry , Hydrazones/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , DNA/drug effects , Doxorubicin/chemical synthesis , Doxorubicin/chemistry , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Mitochondrial Membranes/drug effects , Molecular Conformation , Plasmids/drug effects , Reactive Oxygen Species/metabolism , Stereoisomerism , Structure-Activity Relationship , Time Factors , Tumor Cells, CulturedABSTRACT
Ru(eta6-arene) complexes of epidermal growth factor receptor (EGFR) inhibiting tyrphostins 1a and 1b were prepared, characterized and tested for DNA interaction and bioactivity in four human tumor cell lines. The intrinsic cytotoxicity and cell line selectivity of o-hydroxyanisol 1a was greatly enhanced in its Ru(eta6-p-cymene) complex 2a and in its Ru(eta6-toluene) complex 3a. Complex 2a was particularly efficacious against multi-drug resistant EGFR(+) MCF-7/Topo breast carcinoma cells and also against mTOR-dependent EGFR(-) HL-60 leukemia cells. Complex 3a showed enhanced activity only against 518A2 melanoma cells and HL-60 cells, which are both known to express the mTOR protein. DNA was strongly metallated (ca. 1.7-2%) by all new Ru complexes without undergoing topological changes. Apparently, by complexation to Ru fragments tyrphostin derivatives can address additional biological targets in a manner instrumental to antitumoral strategies.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Organometallic Compounds/pharmacology , Ruthenium/chemistry , Tyrphostins/chemistry , Tyrphostins/pharmacology , Animals , Cell Proliferation/drug effects , DNA/drug effects , DNA/metabolism , Drug Discovery , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Male , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Salmon , Spermatozoa/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
An overview of conjugates of coordination complexes and organometallic complexes of Pt, Ru, Fe, Re, lanthanoids and other metals with natural and synthetic estrogens and antiestrogens targeting the nuclear estrogen receptors is provided. These conjugates are used as targeted cytotoxic agents or - if radiolabeled - as imaging probes for the detection of estrogen receptor-rich tissues such as hormone-dependent tumours. They are assessed with respect to their estrogen receptor binding affinities, potential synergistic cytotoxic effects in cancer cells and their specificity for tumour over non-malignant cells and tissues. The mechanisms of their modes of action are discussed. Pertinent literature is covered up to 2008.