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Anti-cancer agents in medicinal chemistry [journal]
- Histone Deacetylase Inhibitors and Colorectal Cancer: What is New? [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 18.
Colorectal cancer is the third most common cancer in women and men. Cancer was always regarded as a disease of genetic defects such as gene mutations and deletions, chromosomal abnormalities, which lead in the loss of function of tumor-suppressor genes and/or gain of function or hyperactivation of oncogenes. Modifications on chromatin are considered to be the result of the opposing activities of histone acetyltransferases and histone deacetylases, which affect gene expression. Targeting histone deacetylases, histone deacetylase inhibitors are promising agents, as in solid tumors they are characterized by relative low toxicity profile and antiproliferative activities. In colorectal cancer the current experience is at a large part only experimental but promising. Histone Deacetylase Inhibitors are currently being admitted as monotherapy or combination either with the conventional chemotherapy or with other agents. Valproic acid combined with ionization may enhance tumor response. Vorinostat was the first drug of this group used in clinical trial together with conventional chemotherapy and managed to stabilize advanced colorectal cancer. Experimental results show that Vorinostat together with decitabine (DNA methyl transferase inhibitor) may have optimal results. However, patients with colorectal cancer need to be recruited in clinical trials in order to evaluate the potential efficiency of these agents.
- Pro-Oxidative Action of Polyphenols as Action Mechanism for their Pro-Apoptotic Activity. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 22.
Polyphenols, secondary metabolites widely present in plant kingdom, are known for their positive effects on human health, such as treatments of degenerative disease and cancer. Many dietary polyphenols show anti-inflammatory, immunomodulatory and anti-oxidant properties and they are proposed as chemopreventive agents for many skin disorders and cancer. Exposure to solar UV radiation is widely considered to cause skin cancer and a consistent carcinogenic dose derives from UVA, causing several skin disorders as consequence of free radicals generation and DNA damages. Polyphenols, secondary metabolites widely present in plant kingdom, are known for their positive effects on human health, such as treatments of degenerative disease and cancer. Many dietary polyphenols show anti-inflammatory, immunomodulatory and anti-oxidant properties and they are proposed as chemopreventive agents for many skin disorders and cancer. Exposure to solar UV radiation is widely considered to cause skin cancer and a consistent carcinogenic dose derives from UVA, causing several skin disorders as consequence of free radicals generation and DNA damages. In this study, verbascoside, isoverbascoside and tyrosol were investigated for their effect on HEKa (Human Epidermal Keratinocytes adult) cell cultures challenged from UVA-rays. Non-toxic doses of each polyphenol were assayed on HEKa before, during and after the exposure to a damaging dose of UVA: the treatment on HEKa UVA-irradiated caused a decrease of cell viability. Treatment with polyphenols before and after the UVA-irradiation exerted a pro-oxidant effect, while the simultaneous treatment caused a weak decrease of ROS production. The increasing of ROS levels was associated with a pro-apoptotic effect on HEKa, detected by AnnexinV/Propidiun Iodide, mainly evident in surviving cells treated with the polyphenols after the UVA-irradiation. The pro-apoptotic effect was confirmed by the immunodetection of significant changes in the Bax and Bcl-xL protein levels, leading to apoptotic events. The hypothesis that these polyphenols could trigger the apoptosis pathway mainly in UVA-damaged cells, via ROS increase, is here proposed as action mechanism behind their protective effect.
- Growth Inhibition of Various Human Cancer Cell Lines by Imperatorin and Limonin from Poncirus Trifoliata Rafin. Seeds. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 22.
We examined the anticancer effect of limonin and imperatorin on various human cancer cells by MTT assay, and the results showed that imperatorin inhibited the cell growth of SNU 449 (liver cancer) and HCT-15 (colon cancer) cells in a dose-dependent manner, while limonin had less effect. Exposure of different concentrations of limonin and imperatorin caused morphological changes in cancer cells, but not in normal dermal fibroblast cells. Limonin and imperatorin induced apoptotic cell death concurrent with cell cycle arrest in SNU 449 and HCT-15 cells. Limonin and imperatorin up regulate pro-apoptotic protein Bax expression and down regulate anti-apoptotic protein Bcl-2 expression in a dose-dependent manner in HCT-15 and SNU 449 cells. In conclusion, our data demonstrate that limonin and imperatorin have anticancer potential which is associated by promoting cell apoptosis through expression of apoptosis-related proteins.
- HUHS1015 Induces Necroptosis and Caspase-Independent Apoptosis of MKN28 Human Gastric Cancer Cells in Association with AMID Accumulation in the Nucleus. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 22.
The newly synthesized naftopidil analogue HUHS1015 reduced viability of MKN28 and MKN45 human gastric cancer cells in a concentration (0.3-100 µM)-dependent manner, with the potential greater than that for naftopidil. In the cell cycle analysis, HUHS1015 significantly increased the proportion at the subG1 phase of cell cycling in MKN28 cells. In the flow cytometry using propidium iodide (PI) and annexin V, HUHS1015 significantly increased the populations of PI-positive/annexin V-negative and PI-positive/annexin V-positive MKN28 cells, corresponding to primary necrosis and late apoptosis/secondary necrosis, respectively. HUHS1015-induced MKN28 cell death was attenuated by the necroptosis inhibitor Nec-1. In the enzymatic caspase assay, caspase-3, -4, -8, and -9 was not sufficiently activated by HUHS1015. HUHS1015 increased nuclear localization of apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), without affecting expression of the AMID mRNA and protein in MKN28 cells. HUHS1015 caused nuclear fragmentation and condensation in MKN28 cells treated with HUHS1015. Taken together, these results of the present study indicate that HUHS1015 induces both necroptosis and caspase-independent apoptosis of MKN28 cells, possibly the latter effect being due to AMID accumulation in the nucleus.
- Editorial: emerging concepts and therapeutics strategies for the treatment of brain tumors. [Journal Article]
- Anticancer Agents Med Chem 2014; 14(8):1063-4.
"There is no satisfactory treatment of glioblastoma multiforme of the brain" was the introductory sentence of an article published in 1967 by Jelsma & Bucy . Unfortunately this poor prognosis has not changed during the last 45 years and this pessimistic statement remains largely valid. At that time the 5 years survival was less than 10%. A historical comparison of Kaplan-Meier survival plots made in 2000 by Dr. Eric Holland showed that about 90% of patients died within 5 years. Due to the poor prognosis of patients GBM has been called "the Terminator" . Since its introduction in 2005, temozolomide (TMZ) has become the standard treatment despite the fact that the 5 years survival rate modestly increased around 20% . As in 2010, TMZ in selected groups of patients had limited benefit . Kast et al, pointed out that the 22 clinical trials reported in 2012 using drugs that showed promising potential in preclinical studies were found to minimally improve quality of life and overall survival when compared to the "Stupp protocol" . In this hot topic issue we highlight few exciting areas that may provide useful ways to understand the complexity of glioma biology and its implication for the development of novel effective therapeutic strategies. Like in other cancers, the isolation of putative cancer stem cells (GSCs) in glioma cell lines and fresh specimens were received with great enthusiasm. The review by Alexandru et al "Selective Therapeutic Targeting of Malignant Glioma Stem Cells"  discusses the current therapeutic modalities for glioma treatment and highlights the potential underlying mechanism(s) for resistance to radiation and TMZ attributed to the presence of GSCs. Later on, the authors provide a list of potential targets that could be exploited to overcome the inherent resistance of GSCs. The list included microenvironemental factors (hypoxia), signaling pathways (Notch, Hedgehog - GLI, Epidermal growth factor receptor (EGFR), transforming growth factor beta (TGFβ), platelet derived growth factor receptor (PDGFR)), the c-Myc oncogene, the Bmi1 epigenetic silencer gene, overexpression of chemokine receptors, adhesion molecules, bone morphogenic protein (BMP), the stem cell marker CD133, miRNA and potential targets to overcome GSC immune surveillance escape. Some of these promising targets are further discussed in other articles in this hot topic issue. The article "Microenvironment and Brain Tumor Stem Cell Maintenance: Impact of the Niche" by Herold-Mende and Mock  gradually expands our understanding of the complexity of gliomas and provides additional therapeutic targets: the interactions with stromal cells, immune cells, their adjacent endothelial cells and the extracellular matrix. Immune targeting therapies are also likely to benefit from a better understanding of glioma biology related to cancer stemness. It was recently found that the cancer stem cell subtype classified as CD133+ CSCs (proneural-like CSCs) or CD133- CSCs (mesenchymal-like CSCs) may determine the response to immunotherapy and survival . The original research article "Tapasin and human leukocyte class I dysregulation correlates with survival in glioblastoma multiforme" by Thuring et al, adds additional support correlating the dysregulation of tapasin and human leukocyte class I with survival of patients with GBM . The influence of HLA-2 antigen presentation and tapasin is discussed in detail in the review by Darabi et al., "HLA-I antigen presentation and tapasin influence immune responses against malignant brain tumors - considerations for successful immunotherapy", that brings discussion on IFNγ therapy, cytostatics and irradiation . Successful treatment of gliomas would likely require multimodality treatments and thus a better integrated knowledge of glioma biology is essential. The article "Translational gap in glioma research" by Ma et al.  raises awareness of the poor success on translating basic research into clinical trials. The potential of local delivery and nanodrugs-based therapies as way to increase the effectiveness of anticancer drugs and overcome the blood brain barriers is reviewed in the article "Overcoming the blood-brain barrier for chemotherapy: limitations, challenges and rising problems" by Wang et al. . Due to the heterogeneity and complexity of glioma tumors prolonged treatment with high doses of anticancer agents will be necessary to cure cancer. Indeed few attempts has been done recently in this direction: i) a recent study showed that prolonged administration of adjuvant temozolomide improved the survival in adult patients with glioblastoma , ii) a two phase treatment using prolonged high exposure to anticancer drugs (e.g. alkylating agents or DNA replication inhibitors) followed by prolonged esposure to low concentration of salinomycin has been shown in vitro to prevent regrowth of glioma surviving cells [14, 15]. iii) a new proposal to increase overall survival and quality of life include adding already-marketed growth factor-inhibiting drugs to low dose continuous temozolomide . Future improvements in drug delivery either by local or nanoparticles-based therapies in combination with prolonged treatments with less toxic drugs will be important to overcome the challenges due to tumor heterogeneity and the presence of the blood brain barrier. The potential tumorigenic properties of all glioma cancer cells likely due to their plasticity properties and its modulation by the microenvironment that allow interconversion between glioma stem cells and non-glioma stem cells [16-19] is a novel concept that is gradually being accepted as one of the major challenge to completely eradicate the tumor and prevent tumor relapse. The concept that to cure gliomas all cancer cells should be eliminated at once [16, 20] is now replacing the classical belief that cancer stem cells should be the main therapeutic target. For instance Schonberg et al. recently stated "To achieve a brain cancer cure, all tumor cells, particularly the brain cancer stem cells, must be eliminated" . To be successful, other types of therapies not discussed in this hot topic issue but actively investigated (e.g. gene therapy, boron neutron capture therapy) should also take in consideration these novel concepts of glioma biology. At present nobody can predict which type of therapy will be the effective one and therefore any promising strategy is worth pursuing. However, as our knowledge of the complexity of gliomas increases it is likely that a multidisciplinary approach will be more advantageous over a single monotherapy modality. Novel multidisciplinary strategies need to be explored at earlier stages (during the preclinical development) and integrated during early clinical trials to avoid the translational gap of glioma research that if not corrected the prognosis of patients will remain as poor as it has been for the last five decades.
- Berberine Interfered with Breast Cancer Cells Metabolism, Balancing Energy Homeostasis. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 10.
Berberine exerted anti-cancer effect in various cancer cell lines, and was also implied in the treatment of metabolic related diseases. Given the metabolic modulation, we hypothesized that berberine possessed anti-cancer effect under the assistance of metabolic interference. Working as a modulator, metabolic enzyme inhibitor or complex network regulator in energy metabolism was highlighted in current cancer research. A reasonable cross-talk between Chinese medicine and energy homeostasis provided a solid foundation for berberine interference on cancer cells reprogramming metabolism. Our result showed that berberine regulated the reprogramming metabolism through three aspects simultaneously, including mitochondrial oxidative phosphorylation, glycolysis and macromolecular synthesis. This interference with reprogramming metabolism was a continuous, simultaneous and sustainable approach in a moderate mode. And it could be regarded as a gentle and virtuous cycle from a multi-level perspective, indicating an integrated approach in cancer therapy. Meanwhile, we thought that Chinese medicine could link cancer and metabolic related diseases from a dynamic perspective through integrated network pharmacology. This cross-talk would be a realistic and significant strategy for anti-cancer drug discovery and need further investigation in future.
- A Novel Multiple Tyrosine-kinase Targeted Agent to Explore the Future Perspectives of Anti-Angiogenic Therapy for the Treatment of Multiple Solid Tumors: Cabozantinib. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Sep 2.
The process of angiogenesis involves the formation of new blood vessels from pre-existing vasculature by the over expression of certain factors leading to the growth and development of all solid tumor types. Hepatocyte growth factor receptor abbreviated as c-Met and vascular endothelial growth factor abbreviated as VEGF are some of the factors responsible for the induction in tumor growth and development. Recently a number of analogues associated with these receptors are under study. US FDA on November 29, 2012 approved a drug named cabozantinib formerly known as XL184 and which is being marketed under the trade name of Cometriq for the treatment of Medullary Thyroid Cancer (MTC). Design pattern of the drug has been done in such a fashion that it can inhibit both VEGFR2 and c-Met simultaneously without over expressing any of the factors leading to the inhibition of angiogenesis. The drug is still under study for the evaluation of its efficacy in cases of many other solid tumor types including breast cancer, castration resistant prostate cancer (CRPC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer, melanoma, small cell lung cancer (SCLC), ovarian cancer and primary peritoneal or fallopian tube carcinoma. This review article consists of preclinical and clinical data of cabozantinib and its efficacy and safety towards various types of solid tumor types.
- Evaluation of Tricine and EDDA as Co-ligands for 99mTc-Labeled HYNIC-MSH Analogues for Melanoma Imaging. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Aug 25.
Several radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogues have been studied for their abilities to target melanoma tumor cells through specific recognition and binding to the melanocortin receptor 1 (MCR1). In this work, a lactam bridge-cyclized -MSH analogue was labeled with 99mTc via the hydrazinonicotinamide (HYNIC) chelator and characterized for its melanoma tumor targeting properties. The bifunctional chelating agent HYNIC-Boc was attached to the N-terminus of the MSH peptide followed by the lactam cyclization, resulting in the HYNIC-cyc-MSH analogue. The lactam cyclized peptide displayed high affinity and specificity for MC1-receptors present on B16/F1 melanoma tumor cells, exhibiting an IC50 of 6.48 nM. HYNIC-cyc-MSH was radiolabeled with 99mTc using two common co-ligands, tricine and EDDA. In vitro, the radiochemical stability, cell binding and efflux properties were similar between the peptides radiolabeled with tricine and EDDA as co-ligands. In vivo, biodistribution studies (n=4) demonstrated that 99mTc-HYNIC-cyc-MSH/tricine had superior tumor to muscle and tumor to blood ratios than 99mTc-HYNIC-cyc-MSH/EDDA at early time points. Planar gamma imaging of melanoma bearing mice showed that 99mTc-HYNIC-cyc-MSH/tricine was able to clearly visualize tumors, underscoring the potential utility of 99mTc labeled lactam cyclized MSH molecules as melanoma imaging agents.
- New Potent and Selective Inhibitor of Pim-1/3 Protein Kinases Sensitizes Human Colon Carcinoma Cells to Doxorubicin. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Aug 25.
The Pim protein kinases (provirus insertion site of Moloney murine leukemia virus) have been identified as important actors involved in tumor cell survival, proliferation, migration and invasion. Therefore, inhibition of Pim activity by low molecular weight compounds is under investigation as a part of anticancer therapeutic strategies. We have synthesized a series of pyrrolo[2,3-a]carbazole derivatives that significantly inhibited Pim protein kinases at submicromolar concentrations. Particularly, benzodiazocine derivative 1 potently inhibited Pim-1 and -3 isoforms in in vitro kinase assays (IC50 8 nM and 13 nM, respectively), whereas Pim-2 activity was less affected (IC50 350 nM). We show here that no detectable inhibitory effect of 1 was detectable at 1 µM against other 22 serine/threonine and tyrosine kinases. In addition, 1, possessing a planar pyrrolocarbazole scaffold, demonstrated no significant binding to DNA, nor was it a potent topoisomerase I inhibitor, suggesting that 1 is likely to be highly selective for Pim-1 and -3. Importantly, whereas 1 exerted a negligible cytotoxicity for human colon carcinoma HCT116 cell line at concentrations >10 µM within 72 h of cell exposure, it synergized at non-toxic concentrations with the antitumor drug doxorubicin (Dox) in killing HCT116 cells: IC50 of Dox alone and Dox+1 were ~200 nM and ~25 nM, respectively. These data strongly suggest that 1 emerges as a prospective antitumor drug candidate due to its selectivity to individual Pim protein kinases and the ability to potentiate the efficacy of conventional chemotherapeutics.
- Microenvironment and Brain Tumor Stem Cell Maintenance: Impact of the Niche. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2014 Aug 24.
There is a lot of experimental evidence that brain tumors might be sustained by a subpopulation of immature cells, so-called brain tumor stem cells (BTSCs), which do not only drive tumor formation but are highly resistant to conventional therapies. Recent findings suggest a critical role of the molecular and cellular tumor microenvironment in which these cells reside for the maintenance of stem cell properties and therapy resistance. However, detection of different BTSC phenotypes even in the same patient tumor and the observation of a marked plasticity due to instability of the BTSC phenotype caused by the environmental niche have led to a controversial discussion on the validity of the cancer stem cell concept. What complicates the situation even more is that there are different types of niches and little is known about the interplay of the niche components with one another and with different types of BTSCs in the context of stem cell maintenance. In this article we review our current knowledge on different BTSC phenotypes and the cellular components and physiology of the niche in which these cells reside. In addition, we will summarize the molecular and functional interaction of niche cells and niche conditions and how this impacts on BTSC maintenance.