Current Cancer Drug Targets - Volume 14, Issue 5, 2014

Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.

The extensive use of the same chemotherapeutics over several decades has resulted in a growing incidence of chemoresistant cancer cells and secondary malignancies. Therefore, there is an increasing need for new drugs to treat high-risk cancer patients with a higher selectivity for cancer cells and lower toxicity to normal cells. Sulforaphane is released upon hydrolysis of glucoraphanin, a constituent of cruciferous vegetables, by myrosinases that are present in the plant or intestinal microbes. Despite a large number of studies describing the chemopreventive and chemotherapeutic properties of sulforaphane in solid tumors, there is little information on the properties of sulforaphane in hematological malignancies. In this review, we discuss the anti-carcinogenic properties of sulforaphane, the need of higher doses than dietary intake, and the challenges related to testing sulforaphane as an adjunctive agent in combination with the current standard of care for frontline blood cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the excessive deposition of extracellular matrix (ECM), which is thought to contribute to this tumor’s malignant behavior. However, the detailed mechanism and the contribution of excessive deposition of ECM in PDAC progression remain unclear. A better understanding of the mechanism involved in this process is essential for the design of new effective therapies. In this study, we demonstrated that pancreatic cancer cells exhibited increased proliferation and decreased apoptosis in response to type I collagen. In addition, PDAC cells exposed to type I collagen lost the expression of E-cadherin and increased expression of mesenchymal markers, including N-cadherin and vimentin. This epithelial- mesenchymal transition (EMT) was correlated with enhanced cell migration and invasiveness. Knockdown of β1-integrin abolished the effects induced by type I collagen, and further investigation revealed that type I collagen activates β1-integrin (marked by phosphorylation of β1 integrin downstream effectors, focal adhesion kinase [FAK], AKT, and ERK) accompanied by markedly up-regulation of Gli-1, a component of the Hedgehog (HH) pathway. Knockdown of Gli-1 reversed the effects of type I collagen on PDAC invasion and EMT. These results suggest that there is cross-talk between the β1-integrin signaling pathway and the HH pathway in pancreatic cancer and that activation of the HH pathway plays a key role in the type I collagen-induced effects on pancreatic cancer.

For many years, cisplatin has been used to treat many types of cancer, including urogenital, skin and lung cancers. Unfortunately, treatment with this drug causes serious side effects, such as severe toxicity; including nephrotoxicity, neurotoxicity, gastrointestinal toxicity, peripheral neuropathy, ototoxicity, asthenia and hematological toxicity.Therefore, the clinical use of cisplatin has been hampered.The incidence of nephrotoxicity frequently prevents the use of high enough doses to maximize the antineoplastic effects, and strict attention must be given to the hydration of cisplatin-treated patients to minimize kidney damage.Nanobiotechnology, or nanomedicine, was developed to mitigate, or even eliminate,the toxic effects of pharmaceutical compounds; for example, drug-targeting systems were developed to enable site specificity and to control the delivery drug. Therefore, biomedical nanotechnology researchers attempted to develop nanostructures not only to deliver chemotherapeutics to the desired treatment site but also to control when and how quickly the compounds are released. To achieve these ends, a drug can either be encapsulated in a matrix or attached to a particle surface. Studies concerning the encapsulation of cisplatin in liposomes, polymeric nanoparticles, solid lipid nanoparticles and carbon nanotubes, as well as the immobilization of cisplatin on metallic nanoparticles, have already been published. The association of cancer treatment, particularly chemotherapeutics, with nanotechnology is currently one of the most exciting areas of research. In this mini-review, cisplatin will be discussed in terms of its efficacy against many cancers, including bladder cancer. Additionally, established nanostructure-based drug delivery systems for cisplatin and their efficacy against different types of cancer will be reviewed. Because cisplatin is a standard treatment with good performance statistics and with an effective renal function-glomerular filtration rate, we expect that this review will be helpful for future research.

With the recent emergence of novel technologies, the field of biomarker discovery has been the subject of intense research and activity. Major advances in cancer control will be greatly aided by early detection for the diagnosis and treatment of cancer in its pre-invasive state. Cancer being a diverse disease involves alterations in three classes of genes viz. (proto) oncogenes, tumour suppressor genes and DNA repair genes offering a wide variety of opportunities for the development of biomarkers. The emergence of innovative technologies in genomics, proteomics, metabolomics and imaging allows researchers to facilitate inclusive analysis of cancer cells. These approaches have already demonstrated its power to discriminate cancer cells from normal cells and to identify specific genetic elements involved in cancer progression. Cancer evolves via manifold pathways and is a culmination of a variety of genetic, molecular and clinical events. In the past few years, several reports have led to identification of novel cancer signatures via high throughput biology. Current review gives an overview of the bioinformatics tools, cancer database and available software package tools and further summarizes about different strategies involved in Omics research (genomics, proteomics, metabolomics) for the development of cancer biomarkers. We also discuss about the current and emerging biomarkers in breast cancer with fundamental insight into different markers used in breast cancer detection. In addition, we focus upon the systematic integration of various omic data for accelerating cancer biomarker discovery with evidence based cancer management. The above strategies may lead to significant improvement in cancer screening, prognosis and management of therapeutic response in cancer patients.