ABSTRACT
Di(indol-3-yl)methane (=3,3'-methanediyldi(1H-indole), DIM, 1) is a known weakly antitumoral compound formed by digestion of indole-3-carbinol (=1H-indol-3-ylmethanol), an ingredient of various Brassica vegetables. Out of a series of nine fluoroaryl derivatives of 1, three pentafluorophenyl derivatives 2c, 2h, and 2i were identified that exhibited a two to five times greater anti-proliferative effect and an increased apoptosis induction when compared with 1 in the following carcinoma cell lines: BxPC-3 pancreas, LNCaP prostate, C4-2B prostate, PC3 prostate and the triple-negative MDA-MB-231 breast carcinoma. Compound 2h was particularly efficacious against androgen-refractory C4-2B prostate cancer cells (IC50 =6.4â µm) and 2i against androgen-responsive LNCaP cells (IC50 =6.2â µm). In addition, 2c and 2h exhibited distinct activity in three cancer cell lines resistant to 1.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Hydrocarbons, Fluorinated/pharmacology , Indoles/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
BACKGROUND: There is an urgent need for more novel and efficacious therapeutic agents and strategies for the treatment of ovarian cancer - one of the most formidable female malignancies. These approaches should be based on comprehensive understanding of the pathobiology of this cancer and focused on decreasing its recurrence and metastasis. The aim of this study was to evaluate the efficacy of five-year maintenance therapy with indole-3-carbinol (I3C) as well as I3C and epigallocatechin-3-gallate (EGCG) conducted before, during, and after combined treatment compared with combined treatment alone in advanced ovarian cancer. METHODS: Patients with stage III-IV serous ovarian cancer were assigned to receive combined treatment plus I3C (arm 1), combined treatment plus I3C and EGCG (arm 2), combined treatment plus I3C and EGCG plus long-term platinum-taxane chemotherapy (arm 3), combined treatment alone without neoadjuvant platinum-taxane chemotherapy (control arm 4), and combined treatment alone (control arm 5). Combined treatment included neoadjuvant platinum-taxane chemotherapy, surgery, and adjuvant platinum-taxane chemotherapy. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and rate of patients with recurrent ovarian cancer with ascites after combined treatment. RESULTS: After five years of follow-up, maintenance therapy dramatically prolonged PFS and OS compared to control. Median OS was 60.0 months (95% CI: 58.0-60.0 months) in arm 1, 60.0 months (95% CI: 60.0-60.0 months) in arms 2 and 3 while 46.0 months (95% СI: 28.0-60.0 months) in arm 4, and 44.0 months (95% СI: 33.0-58.0 months) in arm 5. Median PFS was 39.5 months (95% СI: 28.0-49.0 months) in arm 1, 42.5 months (95% СI: 38.0-49.0 months) in arm 2, 48.5 months (95% СI: 39.0-53.0 months) in arm 3, 24.5 months (95% СI: 14.0-34.0 months) in arm 4, 22.0 months (95% СI: 15.0-26.0 months) in arm 5. The rate of patients with recurrent ovarian cancer with ascites after combined treatment was significantly less in maintenance therapy arms compared to control. CONCLUSIONS: Long-term usage of I3C and EGCG may represent a new promising way of maintenance therapy in advanced ovarian cancer patients, which achieved better treatment outcomes. TRIAL REGISTRATION: Retrospectively registered with ANZCTR number: ACTRN12616000394448 . Date of registration: 24/03/2016.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers , Combined Modality Therapy , Female , Genes, BRCA1 , Humans , Kaplan-Meier Estimate , Maintenance Chemotherapy , Middle Aged , Neoplasm Grading , Neoplasm Staging , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Proportional Hazards Models , Quality of Life , Treatment OutcomeABSTRACT
In the title of above mentioned article the word 'versatile' had been replaced by 'multifaceted'.
ABSTRACT
BACKGROUND: Recent advances in cancer biology have highlighted the relevance of exosomes and nanovesicles as carriers of genetic and biological messages between cancer cells and their immediate and/or distant environments. It has been found that these molecular cues may play significant roles in cancer progression and metastasis. Cancer cells secrete exosomes containing diverse molecules that can be transferred to recipient cells and/or vice versa to induce a plethora of biological processes, including angiogenesis, metastasis formation, therapeutic resistance, epithelial-mesenchymal transition and epigenetic/stemness (re)programming. While exosomes interact with cells within the tumour microenvironment to promote tumour growth, these vesicles can also facilitate the process of distant metastasis by mediating the formation of pre-metastatic niches. Next to their tumour promoting effects, exosomes have been found to serve as potential tools for cancer diagnosis and therapy. The ease of isolating exosomes and their content from different body fluids has led to the identification of diagnostic and prognostic biomarker signatures, as well as to predictive biomarker signatures for therapeutic responses. Exosomes can also be used as cargos to deliver therapeutic anti-cancer drugs, and they can be engineered to serve as vaccines for immunotherapy. Additionally, it has been found that inhibition of exosome secretion, and thus the transfer of oncogenic molecules, holds promise for inhibiting tumour growth. Here we provide recent information on the diverse roles of exosomes in various cellular and systemic processes governing cancer progression, and discuss novel strategies to halt this progression using exosome-based targeted therapies and methods to inhibit exosome secretion and the transfer of pro-tumorigenic molecules. CONCLUSIONS: This review highlights the important role of exosomes in cancer progression and its implications for (non-invasive) diagnostics and the development of novel therapeutic strategies, as well as its current and future applications in clinical trials.
Subject(s)
Exosomes/physiology , Neoplasms/diagnosis , Neoplasms/therapy , Aging , Biomarkers, Tumor , Cell Communication , Cell Transformation, Neoplastic , Clinical Trials as Topic , Disease Progression , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition , Exosomes/metabolism , Exosomes/ultrastructure , Humans , Immunotherapy , Neoplasm Metastasis , Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. An investigation by Wayne State University identified a discrepancy between the data reported in Figures 1B, 2B and 3C and the original collected data. The investigation committee concluded that this undermined the scientific basis of the publication, that no credible replacement data were available, and advised that the publication should be retracted.
ABSTRACT
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. An investigation by Wayne State University identified a discrepancy between the data reported in Figures 5 and the original collected data. The investigation committee concluded that this undermined the scientific basis of the publication, that no credible replacement data were available, and advised that the publication should be retracted.
ABSTRACT
BACKGROUND: Regenerative medicine aims to provide therapeutic treatment for disease or injury, and cell-based therapy is a newer therapeutic approach different from conventional medicine. Ethical issues that rose by the utilisation of human embryonic stem cells (hESC) and the limited capacity of adult stem cells, however, hinder the application of these stem cells in regenerative medicine. Recently, isolation and characterisation of c-kit positive cells from human amniotic fluid, which possess intermediate characteristics between hESCs and adult stem cells, provided a new approach towards realising their promise for fetal and adult regenerative medicine. Despite the number of studies that have been initiated to characterize their molecular signature, research on developing approaches to maintain and enhance their regenerative potential is urgently needed and must be developed. AIM: Thus, this review is focused on understanding their potential uses and factors influencing their pluripotent status in vitro. CONCLUSION: In short, this cell source could be an ideal cellular resource for pluripotent cells for potential applications in allogeneic cellular replacement therapies, fetal tissue engineering, pharmaceutical screening, and in disease modelling.
Subject(s)
Amniotic Fluid/cytology , Cell Differentiation/physiology , Cell- and Tissue-Based Therapy , Stem Cells/cytology , Animals , Humans , Regenerative Medicine , Tissue Engineering/methodsABSTRACT
The current study utilizes folic acid conjugated poly(styrene-co-maleic anhydride) block copolymer (FA-SMA) to enhance the solubility of a hydrophobic but very potent synthetic curcumin-difluorinated (CDF) analog and its targeted delivery to folate receptor-alpha overexpressing cancers. The nanomicelles showed high aqueous solubility. Importantly, the encapsulation of CDF in nanomicelles resulted in high photo-stability of the otherwise photo-labile drug. When the nanomicelles were tested in folate-receptor overexpressing ovarian and cervical cancer cells they exhibited high anticancer activity causing significant cell population to undergo apoptosis due to upregulation of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibition of nuclear factor kappa-B (NFκB), which further confirmed the targeting ability and anticancer potentials of folate-targeted formulations.
Subject(s)
Curcumin/chemistry , Folic Acid/chemistry , Ovarian Neoplasms , Polymers/chemistry , Uterine Cervical Neoplasms , Apoptosis/drug effects , Cell Line, Tumor , Drug Delivery Systems/methods , Female , Humans , MicellesABSTRACT
Albumin-bound paclitaxel colloidal nanoparticle (Abraxane®) is an FDA approved anticancer formulation available in the market. It is a suspension which is currently used therapeutically for treating cancers of the breast, lung, and pancreas among others. CDF is a novel new and potent synthetic curcumin analogue that is widely used for breast and ovarian cancer. The aim of this study was to use biocompatible albumin as well as folate decorated albumin to formulate colloidal nanoparticles encapsulating curcumin difluorinated (CDF). CDF has demonstrated a 16-fold improvement in stability and remarkable anticancer potency compared to its natural derivative, curcumin. CDF showed marked inhibition of cancer cell growth through down-regulation of multiple miRNAs, up-regulation of phosphatase and tensin homolog (PTEN), and attenuation of histone methyl transferase EZH2. However, CDF is highly hydrophobic and photodegradable with sparing aqueous solubility. In this study, we have formulated albumin nanoparticle using a modified desolvation method, which yielded high CDF loading in a nanoformulation. The physicochemical properties of CDF loaded albumin and folate-decorated albumin nanosuspensions were assessed for particle size, morphology, zeta potential, drug encapsulation efficiency/loading, solubility and drug release. Importantly, the folate ligand decorated albumin nanoparticles were formulated in principle to passively and actively target folate-overexpressing-cancers. In this study, the synthesis and optimization of BSA and folate decorated BSA conjugated CDF nanoparticles are assessed in detail that will be useful for its future clinical translation.
Subject(s)
Antineoplastic Agents/chemistry , Curcumin/analogs & derivatives , Curcumin/chemistry , Folic Acid/chemistry , Nanoparticles/chemistry , Serum Albumin, Bovine/chemistry , Animals , Cattle , Cell Line, Tumor , Cell Survival , Chemistry, Pharmaceutical , Colloids , Drug Carriers , Drug Liberation , Drug Stability , Humans , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Osmolar Concentration , Particle Size , Protein Binding , Solubility , Surface PropertiesABSTRACT
Substituted lawsone Mannich bases 2a-e, 3a-e and 4a-e were prepared and tested for their biological activities. The new fatty alkyl substituted compounds 2a-c exhibited strong and selective growth inhibitory activities in the low one-digit micromolar and sub-micromolar range against a panel of human cancer cell lines associated with ROS formation. In addition, compounds 2a-c revealed sub-micromolar anti-trypanosomal activities against parasitic Trypanosoma brucei brucei cells via deformation of the microtubule cytoskeleton. The N-hexadecyl compound 2c was also highly active against locally isolated Entamoeba histolytica parasite samples exceeding the activity of metronidazole.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Mannich Bases/chemistry , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Cell Line, Tumor , Cytoskeleton/drug effects , Cytoskeleton/metabolism , Drug Design , Entamoeba histolytica/drug effects , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Trypanosoma brucei brucei/drug effectsABSTRACT
Conventional chemotherapy using small molecule drugs is marred by several challenges such as short half-life, low therapeutic index and adverse systemic side effects. In this regard, targeted therapies using ligand directed polyamidoamine (PAMAM) dendrimers could be a promising strategy to specifically deliver anticancer drugs to cancer cells overexpressing complementary receptor binding domains. The aim of this study was to utilize folate decorated PAMAM to enhance the aqueous solubility of a highly hydrophobic but very potent anticancer flavonoid analogue, 3,4-difluorobenzylidene diferuloylmethane (CDF) and to deliver it specifically to folate receptor overexpressing cervical cancer cells (HeLa) and ovarian cancer cells (SKOV3). As compared to the non-targeted formulation, the targeted formulation exhibited significant anticancer activity with higher accumulation in folate receptor overexpressing cells, larger population of apoptotic cancer cells, elevated expression of tumor suppressor phosphatase and tensin homolog (PTEN), and inhibition of nuclear factor kappa B (NFκB) which further confirmed the targeting ability and the promising anticancer activity of the folate based nanoformulation.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Curcumin/analogs & derivatives , Dendrimers/chemistry , Drug Carriers/chemistry , Flavonoids/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Curcumin/chemistry , Curcumin/pharmacology , Diarylheptanoids , Flavonoids/chemistry , Folate Receptor 1/genetics , Folate Receptor 1/metabolism , Folic Acid/chemistry , Folic Acid/metabolism , HeLa Cells , Humans , Molecular Targeted Therapy , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , SolubilityABSTRACT
Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3'-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer.
ABSTRACT
Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer.
Subject(s)
MicroRNAs/genetics , Molecular Targeted Therapy/methods , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Animals , Humans , Pancreatic Neoplasms/drug therapyABSTRACT
This study was conducted to investigate the mechanism of action involved in the anti-cancer activity of daidzein and identification of cancer specific micro-environment as therapeutic target of this secondary metabolite derived from soy. Our data indicated that daidzein induces cellular DNA breakage, anti-proliferative effects and apoptosis in a concentration-dependent manner. We demonstrated that such a daidzein-induced anti-cancer action involves a copper-dependant pathway in which endogenous copper is mobilized by daidzein and redox-cycled to generate reactive oxygen species which act as an upstream signal leading to pro-oxidant cell death. Further in the context of hypoxia being a resistant factor against standard therapies and that an effect secondary to hypoxia is the intracellular acidification, we show that the anticancer activity of daidzein is modulated positively in acidic pH but copper-specific chelator is still able to inhibit daidzein activity. Moreover, an experimental setup of hypoxia mimic (cobalt chloride) revealed an enhanced sensitivity of cancer cells to the cytotoxic effects of daidzein which was neutralized in the presence of neocuproine. The findings support a paradigm shift from the conventional antioxidant property of dietary isoflavones to molecules capable of initiating a pro-oxidant signaling mediated by reactive oxygen species. Further, the clinical relevance of such an action mechanism in cancer chemoprevention is also proposed. This study identified endogenous copper as a molecular target and acidic pH as a modulating factor for the therapeutic activity of daidzein against cancer. The evidence presented highlights the potential of dietary agents as adjuvants to standard therapeutic regimens.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Copper/metabolism , Isoflavones/pharmacology , Reactive Oxygen Species/pharmacology , Cell Hypoxia , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Cleavage , DNA Damage , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Genome, Human , Humans , Hydrogen-Ion Concentration , Oxidation-ReductionABSTRACT
The landscape of cancer has changed considerably in past several years, due mainly to aggressive screening, accumulation of data from basic and epidemiological studies, and the advances in translational research. Natural anticancer agents have always been a part and parcel of cancer research. The initial focus on natural anticancer agents was in context of their cancer chemopreventive properties but their ability to selectively target oncogenic signaling pathways has also been recognized. In light of the rapid advancements in our understanding of the role of microRNAs, cancer stem cells, and epigenetic events in cancer initiation and progression, a number of natural anticancer agents are showing promise in vitro, in vivo as well as in preclinical studies. Moreover, parent structures of natural agents are being extensively modified with the hope of improving efficacy, specificity, and bioavailability. In this article, we focus on two natural agents, 3,3'-diindolylmethane and garcinol, along with 3,4-difluorobenzo curcumin, a synthetic analog of natural agent curcumin. We showcase how these anticancer agents are changing cancer landscape by modulating novel microRNAs, epigenetic factors, and cancer stem cell markers. These activities are relevant and being appreciated for overcoming drug resistance and inhibition of metastases, the two overarching clinical challenges in modern medicine.
Subject(s)
Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/prevention & control , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Curcumin/analogs & derivatives , Curcumin/pharmacology , Dietary Supplements , Epigenesis, Genetic , Epithelial-Mesenchymal Transition/drug effects , Humans , Indoles/pharmacology , MicroRNAs/genetics , Neoplastic Stem Cells/drug effects , Signal Transduction , Terpenes/pharmacologyABSTRACT
Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs (miRNAs) that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition (EMT) characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network-based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents (dietary agents or their synthetic derivatives) can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations (e.g. consumed in the diet) against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance.