Current Cancer Drug Targets - Volume 15, Issue 6, 2015

A major breakthrough in cancer immunotherapy was the discovery of immune checkpoint proteins, which function to effectively inhibit the immune system through various mechanisms. The first of such molecules shown to inhibit both T-cell proliferation and IL-2 production was cytotoxic T-lymphocyte associated protein 4 (CTLA-4). With this discovery, efforts turned to blocking this inhibitory pathway in an attempt to activate dormant T-cells directed at cancer cells. The first antibody directed against CTLA-4, ipilimumab, was quickly ushered into clinical trials and was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 2011. Following the success of ipilimumab, other immune checkpoints were studied as possible targets for inhibition. One such interaction was that of the programmed cell death-1 (PD-1) T-cell receptor and its ligand found on many cancer cells, programmed death-ligand 1 (PD-L1). Unfortunately, the untoward effects of blocking the immune system’s natural inhibitory mechanisms have manifested clinically as diarrhea, rash, and hepatitis. Nevertheless, the exciting field of immune checkpoint inhibitors offers a potential curative option for many cancer patients who previously had a more dismal prognosis. The authors aim to provide a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of cancer and other molecules still in the early development phase.

Sirtuin 1 is a protein deacetylase that regulates a large number of proteins often functionally implicated in tumor development and progression. Its pleiotropic function has turned SIRT1 into an attractive chemotherapeutic target, underscored by very promising preclinical results with SIRT1 inhibitors in the treatment of chronic myeloid leukemia. Here, we revisit the studies on SIRT1 as an emerging target for therapy in pancreatic cancer, a tumor with dismal outcomes for which currently few therapeutic options are available. We highlight those potential SIRT1 target genes that are commonly affected in pancreatic cancer according to recent genomic analyses.

Metastasis to the bone is most frequently observed in advanced cases of breast and prostate cancer. The latent development of overt metastatic lesions is associated with debilitating skeletal morbidity and eventual patient mortality. Secondary tumours in bone are derived from disseminated tumour cells (DTCs) that enter into a state of cellular dormancy. The dormant state confers resistance to conventional chemotherapeutic agents and prevents elimination of DTCs from the bone using current drug therapies. Expansion of our presently limited understanding of the molecular mechanisms underpinning disseminated breast and prostate tumour cell dormancy is critical to the future development of novel drug therapies aimed at the removal of DTCs, and thereby, the prevention of bone metastasis. This review provides an overview of the main putative molecular mechanisms underlying cellular dormancy in breast and prostate cancer bone metastasis reported from multiple experimental in vitro and in vivo models.

It has been shown that the regulatory mechanisms of Ca2+ signaling between tumor and normal cells are different, providing new insight into the pharmacological modulation of anticancer drugs. However, it remains unclear whether there is any difference between hepatoma and normal hepatic cells in their response to extracellular Ca2+ ([Ca2+]e). In the present study, the growth inhibition, apoptosis and necrosis rates of human normal embryo hepatic L02 and human hepatoma HepG2 cells exposed to additional calcium ([Ca2+]a)and adriamycin (ADM), a chemotherapeutic agent to treat hepatocellular carcinoma, were measured by MTT and annexin V/PI assays, respectively. The results showed that the growth inhibition, necrosis and apoptosis rates, as well as intracellular Ca2+ concentrations ([Ca2+]i) induced by [Ca2+]e in HepG2 cells were higher than those in L02 cells. Moreover, [Ca2+]e was able to selectively enhance ADM-induced growth inhibition, apoptosis and necrosis in HepG2 cells, but not in L02 cells. ADM and [Ca2+]a co-treatment had a significant interaction effect to increase [Ca2+]i in both cell lines, although there was no significant difference in [Ca2+]i between the two cells. To further elucidate the mechanisms involved in the selective promotion of [Ca2+]e in HepG2 and L02 cells, the levels of these apoptosis regulatory proteins (bcl-2, bax and procaspase-3) and the caspase-3 activity following treatment of HepG2 and L02 cells with ADM or/and [Ca2+]a were investigated. The results showed that treating HepG2 cells with [Ca2+]a and ADM increased the level of bax protein and caspase-3 activity while decreasing the level of bcl-2 protein, compared with treatment with ADM alone. However, no significant change was noted in L02 cells. These results indicate that hepatoma HepG2 cells are more sensitive to [Ca2+]e than normal hepatic L02 cells and that [Ca2+]a can selectively enhance ADMinduced cell death in HepG2 cells. The mechanism of this intensive pro-apoptotic effect can be ascribed to up-regulation of bax and the simultaneous down-regulation of bcl-2, followed by the switch from procaspase-3 to caspase-3, which executed apoptosis. The present data suggest the potency of the calcium ion as an enhancer of ADM.

Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34+ cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates antiapoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFΚB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics.

(5Z,9Z)-11-Phenylundeca-5,9-dienoic acid was stereoselectively synthesized, based on original cross-cyclomagnesiation of 2-(hepta-5,6-dien-1-yloxy)tetrahydro-2H-pyran and buta-2,3-dien-1-ylbenzene with EtMgBr in the presence of the Cp2TiCl2 catalyst giving 2,5-dialkylydenemagnesacyclopentane in 86% yield. The acid hydrolysis of the product and Jones oxidation of the resulting 2-{[(5Z,9Z)-11-phenylundeca-5,9-dien-1-yl]oxy}tetrahydro-2Н-pyran afforded (5Z,9Z)-11-phenylundeca-5,9-dienoic acid in an overall yield of 75%. A high inhibitory activity of the synthesized acid with respect to human topoisomerase I (hTop1) and II (hTop2α) was detected. Resorting to the data of molecular docking, a mechanism of inhibition was proposed.

Background: The best management of liver metastases from colorectal cancer is still debated and little is known about the true impact of treatments on survival. Materials and Methods: The study involved 122 patients (77 males), aged 64.0 ± 11.0 years (range: 27.8–86.1) at diagnosis of liver metastatization (synchronous in 59). All underwent chemotherapy and at least one procedure of radiofrequency ablation; 53 also had partial hepatic resections. Demographics, tumor characteristics and survival outcomes from liver metastatization were analyzed with univariate and multivariate techniques. This analysis was performed also taking into account relative survival as the best estimate of specific survival. Results: The analysis with observed survival selected the categorized number of involved lymph nodes in the colorectal specimens as the only statistically significant predictor, while the analysis with relative survival also showed site of the primary tumor (above the sigmoid colon or otherwise) and number of liver metastases as significant factors. The standardized mortality ratio was 9.673 (95% CI: 7.668–11.663) and a total of 201.85 years of life were lost in comparison with the survival of the reference population. Conclusions: The computation of relative survival – better than observed survival – selected a more adequate number of predictors, making investigation of even limited series of patients with confounding factors reliable. The finding that prognosis was mainly dependent on the anatomical presentation of the primary tumor and of liver metastases – instead of treatments – could explain the still contrasting opinions on the role of the available therapies in this field.

Aberrant expression of the MDR1-encoded P-glycoprotein (P-gp) is often associated with clinical multi-drug resistance (MDR) leading to poor prognosis and failure of chemotherapy. However, the precise and cooperative molecular mechanism responsible for MDR1 transcription and expression in acquired MDR remains elusive. We, herein, demonstrate that Wnt/β-catenin signal pathway is constitutively activated in Doxorubicin-induced MDR cancer cells, in which nuclear β -catenin specifically interacts with the transcriptional coactivator CBP in a MEK1/2/ERK1/2 signaldependent manner. Specific knockdown of both β-catenin and CBP by RNAi-mediated depletion abrogates MDR1 transcription and expression resulting in a complete reversal of P-gp-dependent efflux function and restoration of sensitivity to the Doxorubincin-induced cytotoxicity. Moreover, following pharmacological disruption of CBP and β - catenin interaction through inhibition of the MEK1/2/ERK1/2 signal by the specific inhibitor PD98059, MDR1 transcription and its encoded P-gp-dependent function are abolished. These findings conclude that the CBP/β-catenin complex is a core component of the MDR1 transcriptional “enhancesome”.

Radiotherapy is one of the important treatment strategies for patients with advanced hepatocellular carcinomas. Developing novel sensitizers for radiotherapy is a key issue due to the low intrinsic radiosensitivity of hepatocellular carcinomas. It was reported the wild-type NBS1 inhibitory peptide (wtNIP) can increase radiosensitivity in several cancer cell lines by abrogating ATM-NBS1 interaction and interrupting cellular DNA damage response. Here, we developed a novel NGRconjugated peptide (NGR-sR9-wtNIP) through coupling the CNGRC angiogenic vessel-homing peptide NGR with the wtNIP peptide. Fusion peptide was tested for internalization, cytotoxicity in Hep3B cells and for tumor localization, and for toxicity in nude mice bearing human hepatocellular carcinomas xenografts. The radiosensitizing activity of NGR-sR9-wtNIP was investigated as well. We found that NGR-sR9-wtNIP can inhibit irradiation induced NBS1 phosphorylation and induce radiosensitization in Hep3B cells. When combined with IR, NGR-sR9-wtNIP suppressed tumor growth obviously in xenograft mice. In addition, the fusion peptide localized in tumor tissue specifically and barely led to any side effects on mice. Taken together, our data strongly suggest that NGRsR9- wtNIP has radiosensitizing potential for radiotherapy of hepatocellular carcinomas.