ABSTRACT
The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism.
Subject(s)
Dietary Supplements/adverse effects , Herb-Drug Interactions , Pharmaceutical Preparations/metabolism , Plant Extracts/pharmacokinetics , Clinical Trials as Topic , Drug Evaluation, Preclinical/methods , Humans , Hypericum/adverse effects , Silybum marianum/adverse effectsABSTRACT
Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.
Subject(s)
Imidazoles/administration & dosage , Lung Neoplasms/drug therapy , Piperazines/administration & dosage , Proto-Oncogene Proteins c-mdm2/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Animals , Carboplatin/administration & dosage , Cell Death/drug effects , Cell Death/genetics , Clinical Trials as Topic , DNA Damage/drug effects , DNA-Binding Proteins/genetics , Disease Models, Animal , Histones/biosynthesis , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/secondary , MCF-7 Cells , Mice , Neoplasm Metastasis , Nuclear Proteins/genetics , Triple Negative Breast Neoplasms/pathology , Tumor Protein p73 , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
BACKGROUND: Resveratrol (RES) inhibits cell growth, induces apoptosis and augments chemotherapeutics in multiple cancer types, although its effects on drug-resistant cancer cells are unknown. MATERIALS AND METHODS: To study the effects of resveratrol in triple-negative breast cancer cells that are resistant to the common cancer drug, paclitaxel, a novel paclitaxel-resistant cell line was generated from the MDA-MB-231 cell line. RESULTS: The resistant MDA-MB-231/PacR cells exhibited a 12-fold increased resistance to paclitaxel. RES treatment reduced cell proliferation and colony formation and increased senescence and apoptosis in both parental and resistant cells. Importantly, RES augmented the effects of paclitaxel in both cell lines. Up-regulation of the MDR1 and CYP2C8 genes were shown to be potential mechanisms of paclitaxel resistance in the resistant cells. CONCLUSION: RES, both alone and in combination with paclitaxel, may be useful in the treatment of paclitaxel-sensitive and paclitaxel-resistant triple-negative breast cancer cells.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Drug Resistance, Neoplasm , Paclitaxel/pharmacology , Stilbenes/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Apoptosis/drug effects , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cellular Senescence/drug effects , Cytochrome P-450 CYP2C8/genetics , Cytochrome P-450 CYP2C8/metabolism , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Inhibitory Concentration 50 , Resveratrol , Survivin , Tumor Stem Cell AssayABSTRACT
Telomeres serve the dual function of protecting chromosomes from genomic instability as well as protecting the ends of chromosomes from DNA damage machinery. The enzyme responsible for telomere maintenance is telomerase, an enzyme capable of reverse transcription. Telomerase activity is typically limited to specific cell types. However, telomerase activation in somatic cells serves as a key step toward cell immortalization and cancer. Targeting telomerase serves as a potential cancer treatment with significant therapeutic benefits. Beyond targeting cancers by inhibiting telomerase, manipulating the regulation of telomerase may also provide therapeutic benefit to other ailments, such as those related to aging. This review will introduce human telomeres and telomerase and discuss pharmacological regulation of telomerase, including telomerase inhibitors and activators, and their use in human diseases.
Subject(s)
Enzyme Inhibitors/therapeutic use , Telomerase/metabolism , Telomere/metabolism , Antineoplastic Agents/therapeutic use , DNA/chemistry , DNA/genetics , DNA/metabolism , Humans , Neoplasms/drug therapy , Plant Extracts/metabolism , Plant Extracts/therapeutic use , Telomerase/genetics , Telomere HomeostasisABSTRACT
Telomerase is a specialized reverse transcriptase that extends and maintains the terminal ends of chromosomes, or telomeres. Since its discovery in 1985 by Nobel Laureates Elizabeth Blackburn and Carol Greider, thousands of articles have emerged detailing its significance in telomere function and cell survival. This review provides a current assessment on the importance of telomerase regulation and relates it in terms of medical genetics. In this review, we discuss the recent findings on telomerase regulation, focusing on epigenetics and non-coding RNAs regulation of telomerase, such as microRNAs and the recently discovered telomeric-repeat containing RNA transcripts. Human genetic disorders that develop due to mutations in telomerase subunits, the role of single nucleotide polymorphisms in genes encoding telomerase components and diseases as a result of telomerase regulation going awry are also discussed. Continual investigation of the complex regulation of telomerase will further our insight into the use of controlling telomerase activity in medicine.
