Current Cancer Drug Targets - Volume 13, Issue 8, 2013

The resistance of tumors to a number of structurally and functionally unrelated chemotherapeutic drugs has been a major obstacle for successful cancer chemotherapy. An important mechanism leading to multidrug resistance (MDR) is the overexpression of the 170 kDa P-glycoprotein (P-gp), which is a member of the ATP-binding cassette (ABC) superfamily of membrane transporters, encoded by the MDR1 gene. Aiming to overcome MDR and due to the clinical failure of P-gp inhibitors, downregulation of MDR1 expression by small molecules has been studied as a possible cancer adjuvant chemotherapy. Here we review the current knowledge on MDR1 gene expression downregulation by small molecules and the mechanisms underlying those effects observed in cancer cell lines, in an attempt to identify targets for future therapeutic interventions.

The aim of this study was to establish the role of serine/threonine protein phosphatase 2A (PP2A) in the survival of leukemic cells from patients with adult T cell leukemia (ATL), associated with human T cell leukemia virus type 1 (HTLV-1). In HTLV-1-infected T cell lines and ATL cells, okadaic acid (OkA), a potent PP2A inhibitor, induced decrease in cell viability and G1 cell cycle arrest by decreasing the expression levels of cyclin D2, cyclin-dependent kinase 4 and cyclin-dependent kinase 6, phosphorylation of pRb, and upregulation of p21, p27 and GADD45α. OkA-induced apoptosis was also due to the suppression of expression of Bcl-2, Bcl-xL and XIAP, and the activation of caspases-3, -8 and -9, and caspase-3 downstream mammalian STE20-like kinase 1 and H2AX. OkA inhibited nuclear factor-kappa B DNA binding and activated mitogen-activated protein (MAP) kinases. Other new PP2A-specific inhibitors, cytostatin and rubratoxin A, also induced decrease in cell viability through caspase-dependent mechanism. MAP kinase inhibitors confirmed the role of p38 MAP kinase in PP2A inhibitors-induced apoptosis. OkA resulted in the generation of reactive oxygen species, and exogenous antioxidant prevented activation of the indicated caspases. Finally, PP2A knockdown inhibited cell growth. The results showed that PP2A inhibition caused reactive oxygen species generation and affected distinct signaling pathways, resulting in the activation of H2AX and subsequent apoptotic cell death. These results suggest that PP2A is a potentially useful target in the treatment of ATL.

Malignant melanoma is an extremely aggressive and metastatic cancer, highly resistant to conventional treatment modalities. Understanding of fundamental mechanisms responsible for its genesis and progression is critical for development of successful chemotherapeutic treatment. It is becoming clear that melanoma results from complex changes in multiple signaling pathways that control cell proliferation and ability to evade the cell death processes. Impairment or hyper-activation of some components of these pathways may lead to malignant transformation and cancer development. In the present review we consider the current data on involvement of such signaling pathways as cyclin/CDK, Ras/Raf/MEK/MAPK, JNK/c-Jun/AP-1, PI3K/Akt/PTEN/mTOR, IKK/I-κB/NF-κB, Wnt/β-catenin, Notch, Jak/STAT, MITF and some growth factors in regulation of the cell cycle progression, apoptosis and development of human cutaneous melanoma. Understanding of molecular aberrations that underlie melanoma oncogenesis is essential for improvement of diagnosis, accurate prognosis assessment, and rational design of effective therapeutics. Inhibitors of these pathways may serve as promising tools for anti-melanoma targeted therapy. Some novel anti-melanoma target drugs are characterized.

Hepatocellular cancer (HCC) is the third cause of death by cancer worldwide. In the current study we target &bgr- catenin, an oncogene mutated and constitutively active in 20-30% of HCCs, via a novel, cell permeable gamma guanidine-based peptide nucleic acid (γGPNA) antisense oligonucleotide designed against either the transcription or the translation start site of the human &bgr-catenin gene. Using TOPflash, a luciferase reporter assay, we show that γGPNA targeting the transcription start site showed more robust activity against &bgr-catenin activity in liver tumor cells that harbor &bgr-catenin gene mutations (HepG2 & Snu-449). We identified concomitant suppression of &bgr-catenin expression and of various Wnt targets including glutamine synthetase (GS) and cyclin-D1. Concurrently, γGPNA treatment reduced proliferation, survival and viability of HCC cells. Intriguingly, an angiogenesis quantitative Real-Time-PCR array identified decreased expression of several pro-angiogenic secreted factors such as EphrinA1, FGF-2, and VEGF-A upon &bgr-catenin inhibition in liver tumor cells. Conversely, transfection of stabilized-&bgr-catenin mutants enhanced the expression of angiogenic factors like VEGF-A. Conditioned media from HepG2 cells treated with &bgr-catenin but not the mismatch γGPNA significantly diminished spheroid and tubule formation by SK-Hep1 cells, an HCC-associated endothelial cell line. Thus, we report a novel class of cell permeable and efficacious γGPNAs that effectively targets &bgr-catenin, a known oncogene in the liver. Our study also identifies a novel role of &bgr-catenin in liver tumor angiogenesis through paracrine mechanisms in addition to its roles in proliferation, survival, metabolism and cancer stem cell biology, thus further strengthening its effectiveness as a therapeutic target in HCC.

Melanoma, a malignant tumor of melanocytes, causes the majority (75%) of all skin cancer-related deaths. The overall efficacy of different anti-cancer therapies on metastatic melanoma is quite limited, due to its high resistance to all forms of conventional treatments, including chemotherapy, radiotherapy and immunotherapy, leading to low patient survival rates. The present review identifies possible strategies for the treatment of advanced melanoma and describes two novel agents, Ipilimumab and Vemurafenib, which may now be useful for clinical practice. Ipilimumab, a humanized, IgG1 monoclonal antibody, acts through immune-modulation since it blocks cytotoxic Tlymphocyte- associated antigen-4 (CTLA-4), producing favourable antitumor immune system responses and reducing tolerance to tumor-associated antigens. Vemurafenib is a novel oral small-molecule kinase inhibitor with high selectivity and efficacy toward a specific mutated oncogenic BRAF-signalling mediator. The mechanism of action of Vemurafenib involves selective inhibition of the mutated BRAFV600E kinase that leads to reduced signalling through the aberrant MAPK pathway. However, as patients commonly develop Vemurafenib resistance, clinical trials of Vemurafenib in combination with Ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with longterm clinical benefits, emphasizing the importance of simultaneously targeting several pathways. As both drugs had only modest effects on median survival, new therapeutic combinations are needed, such as BRAF inhibitors with MEK inhibitors or combinations of immunomodulators and pathway inhibitors. Such strategies should have the potential of maximizing antitumor effect while minimizing and improving clinical benefit. Nevertheless, these two new agents open a promising view into an effective management of melanoma.

Prions are renowned for their role in neurodegenerative diseases in humans and animals. These are manifested as transmissible spongiform encephalopathies (TSEs) that result from the conversion of the normal glycosylphosphatidylinositol (GPI) anchored cellular prion protein (PrPc) to a misfolded, aggregated and pathogenic form, prion protein scrapie (PrPSc) via a post-translational process followed by the accumulation of PrPSc within the central nervous system. New research in this area has demonstrated that PrP is over-expressed in a variety of cancers including gastric, pancreatic and breast cancers, affecting the growth and invasiveness of these cancers as well as playing an important role in the acquisition of multi-drug resistant (MDR) gastric cancer. Prion-like doppel protein (Dpl), sharing 25% amino acid sequence homology to PrP and whose function remains elusive, has also been shown to exhibit a high level of expression in a number of cancers including acute myeloid leukemia’ s, myelodysplastic syndromes, gastric adenocarcinoma, anaplastic meningioma and astrocytomas. Furthermore, the tumour suppressor protein, p53, already known for its involvement in cancer development, has recently been shown to display prion-like tendencies. This review provides an overview of prions and prion-like proteins in mammals discussing their structure, function and role in cell function and disease. Furthermore, current research progress on the role of prion/prion-like proteins in the development, progression, and drug resistance of various cancers will be summarized. Potential implications for future development of new therapeutic treatments targeting prion and prion-like proteins will be discussed.