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Current pharmaceutical design [journal]
- Combined modality therapy in pancreatic adenocarcinoma: review and updates on a controversial issue. [Journal Article]
- Curr Pharm Des 2014 Oct 22; 20(42):6697-701.
Due to its extremely high mortality rates, strong efforts continue to be made to develop new therapies in the treatment of pancreatic adenocarcinoma. The use of combined modality chemoradiotherapy for the treatment of pancreatic adenocarcinoma remains an approach with both promise and controversy. This article reviews the conflicting data with regards to role of combined modality therapy in pancreatic adenocarcinoma and provides an update on current studies in the field.
- Curcumin in combined cancer therapy. [Journal Article]
- Curr Pharm Des 2014; 20(42):6682-96.
The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.
- Mechanism-based Combinations with Pim Kinase Inhibitors in Cancer Treatments. [Journal Article]
- Curr Pharm Des 2014; 20(42):6670-81.
Proviral integration site for Moloney murine leukemia virus (Pim) kinases is a potential therapeutic target in both hematological and solid tumors, and is up-regulated in various cancer types. In certain cases, their expression levels are positively correlated with poor clinical outcome. A number of selective Pim kinase inhibitors are under development and a few are in clinical trials. Investigations of the mechanism of actions of these drugs have demonstrated that by inhibiting Pim kinases, processes such as transcription, translation, cell cycle progression, cell survival and drug resistance are affected. Pim kinases can be upregulated by multiple growth factors, cytokines, and chemokines, which also activate redundant pathways such as phosphatidylinositide 3-kinases/protein kinase B/mammalian targets of rapamycin, and mitogen-activated protein kinases. Interestingly, Pim kinases also share substrates with these parallel pathways. To overcome this challenge, Pim kinase inhibitors were tested in combination with other therapeutic agents based on their unique mechanism of actions. Based on existing literature, we identified studies where Pim kinase inhibitors were part of the combination strategies that used targeted agents or broad-spectrum chemotherapeutic drugs (including FDA-approved agents). The addition of Pim kinase inhibitors to these treatment strategies leads to additive to synergistic cytotoxic effect in cancer cells. Depending on the compound, combination results in sequential or complementary blockage or downregulation of oncogenic pathway. In summary, these studies provide evidence for developing mechanism-based combination therapies with Pim kinase inhibitors to treat cancers.
- Pancreatic cancer: systemic combination therapies for a heterogeneous disease. [Journal Article]
- Curr Pharm Des 2014; 20(42):6660-9.
Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.
- Pharmaco-therapeutic challenges in cancer biology with focus on the immune- system related risk factors. [Journal Article]
- Curr Pharm Des 2014; 20(42):6652-9.
Over the past, progress has always been achieved in therapy of various human diseases with the introduction of novel methodologies from basic to clinical research. Recent advances in techniques, especially DNA sequencing and methylation analyses, faster miniaturized proteomics and live cellular stainings, are opening a new era in cancer research. Perhaps the difference this time can be envisaged as the beginning of the long-sought individualization of forthcoming cancer therapies. Cancer has complex genetic susceptibility that is wider than previously thought. Apart from genes encoding six functional capabilities of cancer - independent growth, avoidance of apoptosis, immortalization, multi-drug resistance, neovascularization, and invasiveness - predisposition includes four more factors that promote genome instability, inflammation, deregulation of metabolism as well as evasion of destruction by the immune system. The underlying genetic events, i.e. base-pair DNA mutations, are not the sole factors in cancer development. Additional novel controls of gene expression have been found in the epigenetic machinery, which has been increasingly important in assessing cancer risk in recent years. The predisposing factors, including their regulatory elements, are bona fide potential new targets in prospective cancer pharmacotherapy.
- A Comprehensive Review of Poorly Differentiated Neuroendocrine Carcinomas (pdNECs): a Niche to Find Novel Opportunities. [Journal Article]
- Curr Pharm Des 2014; 20(42):6644-51.
Although grouped under the same name, neuroendocrine tumors comprise a heterogeneous family of neoplasms with a wide range of clinical and biological behaviors and responses to different treatment options. Most of the tumors derived from enterochromaffin cells are indolent or at least not as aggressive as epithelial tumors. However, a small percentage of these tumors have a poor prognosis and highly aggressive histology that results in a very short overall survival and scarce treatment options compared with well and moderately differentiated tumors. Patients with poorly differentiated neuroendocrine carcinomas barely exceed 6-8 months of survival. This particular poor risk subgroup of neuroendocrine tumors remains an unmet medical need and becomes a challenge in the daily clinical practice. A deeper knowledge of the biology and novel targeted agents might allow for future clinical development of novel agents in this setting. In this review we summarize the current background behind the management of poorly differentiated neuroendocrine carcinomas in daily clinical practice.
- Immunotoxins Constructed with Ribosome-Inactivating Proteins and their Enhancers: A Lethal Cocktail with Tumor Specific Efficacy. [Journal Article]
- Curr Pharm Des 2014; 20(42):6584-643.
The term ribosome-inactivating protein (RIP) is used to denominate proteins mostly of plant origin, which have N-glycosidase enzymatic activity leading to a complete destruction of the ribosomal function. The discovery of the RIPs was almost a century ago, but their usage has seen transition only in the last four decades. With the advent of antibody therapy, the RIPs have been a subject of extensive research especially in targeted tumor therapies, which is the primary focus of this review. In the present work we enumerate 250 RIPs, which have been identified so far. An attempt has been made to identify all the RIPs that have been used for the construction of immunotoxins, which are conjugates or fusion proteins of an antibody or ligand with a toxin. The data from 1960 onwards is reviewed in this paper and an extensive list of more than 450 immunotoxins is reported. The clinical reach of tumor-targeted toxins has been identified and detailed in the work as well. While there is a lot of potential that RIPs embrace for targeted tumor therapies, the success in preclinical and clinical evaluations has been limited mainly because of their inability to escape the endo/lysosomal degradation. Various strategies that can increase the efficacy and lower the required dose for targeted toxins have been compiled in this article. It is plausible that with the advancements in platform technologies or improved endosomal escape the usage of tumor targeted RIPs would see the daylight of clinical success.
- Combined cancer therapy: strategies to overcome acquired aromatase inhibitor resistance. [Journal Article]
- Curr Pharm Des 2014 Oct 22; 20(42):6575-83.
Aromatase inhibitors (AIs) have become one of the mainstays of treatment of postmenopausal women with hormone receptorpositive breast cancer. However, acquired resistance to treatment continues to be a significant clinical challenge. There is increasing evidence from preclinical studies that activation of growth factor signaling pathways, as well as cross-talk between these pathways and estrogen receptor-alpha signaling pathways are important mechanisms that contribute to AI resistance. These preclinical studies have been the foundation for multiple randomized clinical trials that have evaluated combination targeted therapy in patients with advanced breast cancer. While the clinical benefit observed in these trials has been variable, the preclinical studies were successful in predicting clinical outcomes. This review focuses on mechanisms of acquired AI resistance and describes preclinical studies that have evaluated combination targeted therapy to overcome AI resistance, as well as clinical trials that have translated this information to the clinical setting.
- NCRNA Combined Therapy as Future Treatment Option for Cancer. [Journal Article]
- Curr Pharm Des 2014; 20(42):6565-74.
Cancer initiation and progression are governed by a complex multistep process in which successive alterations accumulate in multiple protein-coding and noncoding genes. MicroRNAs are an evolutionarily conserved class of endogenous 19- to 24-nucleotide noncoding RNAs that have been validated as key players in the balance of most cellular processes, including drug resistance. MicroRNAs change the output of protein-coding genes through posttranscriptional regulation by binding in a sequence-specific manner to the transcripts of their target genes. Resistance to therapy remains a major challenge in cancer treatment; clear solutions to this problem have yet to be found, in spite of intensive research in recent years. In this review, we explore the concept of cancer multitherapy using noncoding RNAs. We also address basic scientific questions that are related to personalized cancer treatment.
- The Exploitation of Toll-like Receptor 3 Signaling in Cancer Therapy. [Journal Article]
- Curr Pharm Des 2014; 20(42):6555-64.
Toll-like receptors (TLRs) are a group of transmembrane receptors that recognize molecular motifs of pathogen origin and activate immune response. Although TLRs were first identified in immune system cells, recent studies show they can also be expressed in tumor cells. TLR3 recognizes dsRNA or its synthetic ligand poly (I: C) and is responsible primarily for the defense against viral infections. Recent studies showed that TLR3 can trigger apoptosis in cancer cell. Furthermore, other dsRNA binding receptors (MDA5 and RIG-I), localized in cytoplasm, can also bind poly (I: C) and therefore contribute to this effect. With TLR3's capacity to induce apoptosis and activate the immune system at the same time, TLR3 ligands are an attractive therapeutic option for treatment of cancer. Novel therapies include combining poly (I: C) with other components such as chemotherapeutics, apoptosis enhancers, other TLR ligands and peptides activating the immune system. Slightly modified TLR3 agonists (Ampligen®, Hiltonol®, poly IC-LC) are already being used in clinical studies for cancer therapy as single agents or in combination with other drugs. On the other hand, latest studies forewarn that TLR3 activation can also have tumor promoting role so it is crucial to identify the terms by which TLR3 has pro-tumor/anti-tumor effect in order to safely implement TLR3 ligand based therapy into clinical trials.