Current Cancer Drug Targets - Volume 15, Issue 7, 2015

Drug resistance primarily appears where there is altered drug metabolism or target modification. It is a major challenge in cancer therapy which affects treatment process, and limits chemotherapeutics. Recently, nanotechnological approaches were shown to be capable of lowering drug side effects and protecting from enzymatic degradation. Therefore, patient’s compliance and survival rate have dramatically increased. This review elaborates on the structures and functions of the factors involved in cancer drug resistance together with nanobiotechnological approaches for overcoming the obstacles in breast cancer research and therapy. The present paper provides information and suggestions to both basic and clinical researchers to develop new nanobiotechnological methods to improve breast cancer modalities especially in drug resistance.

Parathyroid tumors are almost invariably associated with parathormone (PTH) hypersecretion resulting in primary (PHPT) or secondary (SHPT) hyperparathyroidism. PHPT is the third most common endocrine disorder with a prevalence of 1-2% in post-menopausal women; SHPT is a major complication of chronic kidney failure, the prevalence of which is increasing. The calciumsensing receptor (CASR) is the key molecule regulating PTH synthesis and release from the parathyroid cells in response to changes in extracellular calcium concentrations. A potent calcimimetic, cinacalcet, has been developed in the last ten years and made available for medical treatment of both PHPT and SHPT. Cinacalcet has been demonstrated to be effective in inhibiting PTH secretion, though the drug fails to normalize PTH release, both in PHPT and SHPT patients with different degrees of disease severity, including patients with parathyroid carcinomas and with MEN1-related parathyroid tumors. Here we reviewed the molecular aspects of CASR target therapy and the effect of the CASR gene single nucleotide polymorphisms. Clinical data concerning the efficacy and safety of cinacalcet in controlling hyperparathyroidism are reported, focusing on the treatment of the different types of parathyroid tumors. Finally, limits of this target therapy are analyzed, pointing out the lack of efficacy in improving kidney and bone morbidities in PHPT and cardiovascular diseases in SHPT. Though cinacalcet is a target therapeutic option for parathyroid tumors, further approaches are warranted to fully control these metabolic disorders and the underlying tumors.

The integrity of eukaryotic cellular function depends on molecular and biochemical compartmentalization. The transport of macromolecules between compartments requires specific and energydriven mechanisms. It occurs through a class of transport proteins known as karyopherins, which are divided in three different groups (exportins, importins, and transportins). The ubiquitous exportin Chromosome Region Maintenance 1 (CRM1) is involved in the transport of many proteins and RNA molecules from nucleus to cytoplasm. We have reviewed the available evidence supporting the relevance of CRM1 in the biology of several human neoplasms, its potential role in drug resistance, and its promise as a therapeutic target. Here we discuss different cancer related proteins (tumor suppressor genes, oncogenes, and enzymatic therapeutic targets), their function, and their association with CRM1, as well as agents that specifically inhibit CRM1, their mechanism of action, and their clinical relevance in certain human neoplasms. The directionality of nuclear transport and the specific molecular cargo in question are of paramount importance when examining the effects that CRM1 inhibition may have on cellular pathophysiology. The available data point out the potential role of CRM1-dependent nuclear export of regulatory proteins in the biology of certain human malignancies. Further studies should expand and clarify the importance of this mechanism in the pathobiology of human neoplasia.

Thymic neoplasms are rare malignant tumors, and the mainstay of treatment for patients with thymic tumors is surgical resection. Chemotherapy is necessary for patients with extensive tumor invasion or metastasis who are unable to undergo complete radical excision. However, only two-thirds of these patients respond to chemotherapy. For those patients who are resistant to chemotherapy, targeted therapy has been proposed as a beneficial alternative. Many genes implicated in tumorigenesis and metastasis have been demonstrated to be therapeutic targets in thymic malignancies. Currently, a number of case reports and small clinical trials have reported that a few inhibitors, such as sorafenib and sunitinib, are effective for the treatment of thymoma. This review describes the current potential drug targets and their roles in the development of thymic malignancy. Drugs that are used for the targeted therapy of thymoma and the results of related clinical trials are addressed. Furthermore, we provide an overview of the screening of specific patients who are suitable for targeted therapy and the efficacy of targeted therapy in patients with refractory or recurrent thymic tumors.

Intratumoral delivery of drugs, enabling increased local concentrations in the tumor microenvironment, might be superior to systemic administration in promoting antitumor activity and minimizing the systemic side effects of some drugs. Unfortunately, not all human cancers are amenable to drug injection into the tumor site. Lung cancers are candidate tumors for taking advantage of local delivery, being accessible via the endobronchial space by aerosol administration. Inhalation of aerosolized drugs is a promising option in the management of lung diseases and currently represents the standard treatment for asthma and chronic obstructive pulmonary disease. Besides a high local concentration, the advantages of aerosol administration of medications to the lung include reduced distribution to the systemic circulation and pain- and needle-free delivery. Several therapeutic agents have been explored for inhalation in lung malignancies, including chemotherapeutic agents, cytokines, Toll-like receptor agonists, monoclonal antibodies, genes and antisense oligonucleotides, demonstrating the feasibility of aerosol delivery, the potential antitumor effects and the reduced side effects compared with systemic treatment. In this review we summarize preclinical and clinical data regarding aerosol delivery of these drugs in the treatment of lung cancer.

Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease worldwide. Although significant improvement has been made in understanding its pathophysiology, only small portion of patients with PDA are likely to benefit from curative surgery and current chemotherapy. Thus, there is an urgent need for developing novel effective therapeutic approaches to the treatment of PDA. Today, garlic products have become an important source of effective compounds for the treatment of cancer. We have recently identified a novel garlic active component, S-propargyl-L-cysteine (SPRC), an analogue of S-Allyl Cysteine (SAC). Although its anticancer activity has been shown against several cancers, the mechanism of action is not fully understood. The present study was first designed to determine the anticancer activity of SPRC in PDA and the underlying mechanisms of action in vitro and in vivo. Our results demonstrated that SPRC reduced cell viability and colony formation, inhibited cell proliferation, induced G2/M phase cell cycle arrest and apoptosis in human PDA cells with various p53 statuses (HPAC, p53 wt; Panc-1, p53 mt). Furthermore, SPRC inhibited tumor growth in Panc-1 xenograft models. We also demonstrated that SPRC achieved its anticancer effects by regulation of the JNK protein levels through increasing its phosphorylation and decreasing its polyubiquitination-mediated degradation. In conclusion, SPRC has significant anti-PDA activity and the effects do not depend on p53 status, presumably through activating the JNK signaling pathway, providing a basis for the development of this compound as a novel target anticancer therapeutic agent for PDA.

High grade gliomas (HGG) are usually associated with a very dismal prognosis, which was moderately improving in the last decade with the introduction of the alkylating agent temozolomide in their treatment. The methylation status of MGMT (O6 methylguanine DNA-methyltransferase) promoter is one of the strongest predictive and prognostic factors for the patient chemoresponse. For instance, the molecular method of assessment for MGMT promoter status is not standardized. In this background, we developed a fluorescent capillary gel electrophoresis-based methylation specific-PCR. This technique allowed a semi-quantitative estimate of the relative ratio between methylated and unmethylated alleles. The efficacy and accuracy of the technique was assessed in a retrospective cohort of 178 newly diagnosed adult HGGs, who were homogeneously treated. First, we analyzed the impact on survival of different cut-off points in the MGMT promoter methylation and, to go further, we correlated these different rates to other well-known prognostic molecular factors involved in adult HGGs. This strategy allowed to validate our technique as a very sensitive technique (detection of a low methylation percentage, < 5%), which was feasible in fresh-frozen as well as in FFPE samples and had the propensity to detect intra-tumor heterogeneity. This technique identified a new sub-group of anaplastic oligodendrogliomas or oligoastrocytomas defined by a minor methylation and a worse outcome and, therefore, will help to substratify accurately into more homogeneous subgroups of methylated tumors.