Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 14, Issue 9, 2014

As early as the 1920s, the eminent physician and chemist, Otto Warburg, nominated for a second Nobel Prize for his work on fermentation, observed that the core metabolic signature of cancer cells is a high glycolytic flux. Warburg averred that the prime mover of cancer is defective mitochondrial respiration, which drives a switch to an alternative energy source, aerobic glycolysis in lieu of Oxidative Phosphorylation (OXPHOS), in an attempt to maintain cellular viability and support critical macromolecular needs. The cell, deprived of mitochondrial ATP production, must reprogram its metabolism as a secondary survival mechanism to maintain sufficient ATP and NADH levels for macromolecule production, membrane integrity and DNA synthesis as well as maintenance of membrane ionic gradients. A time-tested method to identify and disrupt criminal activity is to “follow the money” since the illicit proceeds from crime are required to underwrite it. By analogy, strategies to target cancer involve following and disrupting the flow of ATP and NADH, the energetic and redox “currencies” of the cell, respectively, since the tumor requires high levels of ATP and NADH, not only for metastasis and proliferation, but also, on a more basic level, for survival. Accordingly, four broad ATP reduction strategies to impact and potentially derail cancer energy production are highlighted herein: 1) small molecule energy-restriction mimetic agents (ERMAs) that target various aspects of energy metabolism, 2) reduction of energy ‘subsidization’ with autophagy inhibitors, 3) acceleration of ATP turnover to increase energy inefficiency, and 4) dietary energy restriction to limit the energy supply.

Over the past few years, modern medicinal chemistry has evolved towards providing us new and alternative chemotherapeutic compounds with high cytotoxicity towards tumor cells, alongside with reduced side effects in cancer patients. Organometallic compounds and their unique physic-chemical properties typically used in homogenous catalysis are now being translated as potential candidates for medical purposes. Their structural diversity, ligand exchange, redox and catalytic properties make them promising drug candidates for cancer therapy. Over the last decade this area has witnessed a steady growth and a few organometallic compounds have in fact already entered clinical trials, emphasizing its increasing importance and clinical relevance. Here we intend to stress out the different applications of organometallic compounds in medicine with emphasis on cancer therapy, as well as address setbacks regarding formulation issues, systemic toxicity and off-target effects. Advantages over classical coordination metal complexes, their nanovectorisation and specific molecular targets are also discussed.Cancer therapy, clinical trials, M-arenes, M-carbenes, M-carbonyls, metallocenes, nanovectorisation, organometallics compounds.

Indirubin is an active ingredient mainly used to treat leukemia in China and is reported to be a leading inhibitor of cyclindependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) by competing with ATP binding sites. New findings have indicated that its comprehensive structure may contribute to its polypharmacological activities particularly in cancer and neurodegenerative disease therapy, as both of these diseases are usually accompanied by a common molecular link related to abnormal phosphorylation of CDKs and GSK-3. In the elderly, cancer and neurodegenerative disease are tightly associated common diseases and sometimes unavoidably coexist. In this review, the underlying mechanisms of the dual actions of indirubin and its structurally-related compounds in cancer and neurodegenerative disease therapy are presented.

Colorectal cancer is the third most common cancer in humans. Cancer has always been regarded as a disease of genetic defects such as gene mutations and deletions, chromosomal abnormalities, which lead to 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 relatively low toxicity profile and antiproliferative activities. In colorectal cancer, the current experience is mainly experimental but promising. Histone deacetylase inhibitors are currently being admitted as monotherapy or combination therapy 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 in combination with conventional chemotherapy and managed to stabilize advanced colorectal cancer. Experimental results show that combination therapy of vorinostat and decitabine (DNA methyl transferase inhibitor) may have optimal results. However, patients with colorectal cancer need to be recruited in randomized clinical trials in order to evaluate the potential efficiency of these agents.

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 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 nontoxic 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.

Plants are fantastic sources for present day life saving drugs. Monocrotaline a natural ligand exhibits dose-dependent cytotoxicity with potent antineoplastic activity. This study was intended to disclose the therapeutic potential of monocrotaline against hepatocellular carcinoma. The in silico predictions have highlighted the antineoplastic potential, druglikeness and biodegradability of monocrotaline. The in silico docking study has provided an insight and evidence for the antineoplastic activity of monocrotaline against p53, HGF and TREM1 proteins which play a threatening role in causing hepatocellular carcinoma. The mode of action of monocrotaline was determined experimentally by in vitro techniques such as XTT assay, NRU assay and whole cell brine shrimp assay have further supported our in silico studies. The in vitro cytotoxicity of monocrotaline was proved at IC50 24.966 µg/mL and genotoxicity at 2 X IC50 against HepG2 cells. Further, the credible druglike properties with non-mutagenicity, non-toxic on mammalian fibroblast and the potential antineoplastic activity through in vitro experimental validations established monocrotaline as a novel scaffold for liver cancer with superior efficacy and lesser side effects.

Background: Blocking vascular endothelial growth factor (VEGF) mediated tumor angiogenesis by phytochemicals has emerged as an attractive strategy for cancer prevention and therapy. Methods: We investigated the anti-angiogenic effects of ellagic acid in a hamster model of oral oncogenesis by examining the transcript and protein expression of hypoxia-inducible factor-1alpha (HIF-1α), VEGF, VEGFR2, and the members of the PI3K/Akt and MAPK signaling cascades. Molecular docking studies and cell culture experiments with the endothelial cell line ECV304 were performed to delineate the mechanism by which ellagic acid regulates VEGF signaling. Results: We found that ellagic acid significantly inhibits HIF-1α-induced VEGF/VEGFR2 signalling in the hamster buccal pouch by abrogating PI3K/Akt and MAPK signaling via downregulation of PI3K, PDK-1, p-Aktser473, mTOR, p-ERK, and p-JNK. Ellagic acid was also found to reduce the expression of histone deacetylases that could inhibit neovascularization. Analysis of the mechanism revealed that ellagic acid inhibits hypoxia-induced angiogenesis via suppression of HDAC-6 in ECV304 cells. Furthermore, knockdown of endogenous HDAC6 via small interfering RNA abrogated hypoxia-induced expression of HIF-1α and VEGF and blocked Akt activation. Molecular docking studies confirmed interaction of ellagic acid with upstream kinases that regulate angiogenic signaling. Conclusions: Taken together, these findings demonstrate that the anti-angiogenic activity of ellagic acid may be mediated by abrogation of hypoxia driven PI3K/Akt/mTOR, MAPK and VEGF/VEGFR2 signaling pathways involving suppression of HDAC6 and HIF-1α responses. General Significance: Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key oncogenic signaling cascades and HDACs.

In this article, the synergistic effects of WP 631 and epothilone B (Epo B) combination in human ovarian cancer cells (SKOV-3) cells are investigated and the reasons for the exact mechanisms of action of both drugs co-administered are explained. Compared with single drugs, the combination treatment significantly enhances apoptosis as confirmed by increases in caspases (-8, -9, -3) activity, ROS level and DNA damage and decreases in mitochondrial membrane potential. The combination of the compounds activated both caspase - 8 and -9, indicates that both pathways of apoptosis, extrinsic (induced by the effect of Epo B) and intrinsic (triggered mainly by WP 631) participate in the proposed treatment. Thus, the results of this study strongly suggest a synergistic action of the combined treatment with WP 631 and Epo B in SKOV-3 cells death induction.

Synthesis, characterization and investigation of antiproliferative activity of eight thiazole-based nitrogen mustard against human cancer cells lines (MV4-11, A549, HCT116 and MCF-7) and normal mouse fibroblast (BALB/3T3) are presented. Their structures were determined using NMR, FAB MS, HRMS and elemental analyses. Among the derivatives, 3a, 3b, 3e and 3h were found to exhibit high activity against human leukemia MV4-11 cells with IC50 values of 0.634-3.61 µg/ml. The cytotoxic activity of compound 3a against BALB/3T3 cells is up to 40 times lower than against cancer cell lines. Our data indicated also that compound 3e had very strong activity against MCF-7 and HCT116 with IC50 equal to 2.32 µg/ml and 2.81 µg/ml, respectively. Their activity was similar to the activity of cis-platin, which is clinically used as anticancer drug in the treatment of human solid tumours. We also perform quantum chemical calculation of interaction and binding energies in complexes of model systems and 3e with DNA bases. Interaction of real drug 3e with guanine is much stronger than with the remaining nucleobases, and the strongest among all investigated complexes. Computer simulations were performed with ATP-binding domain and DNA-binding site of hTopoII. Compounds 3a-h were recognized as potential inhibitors of hTopoII.

A Series of chalcone derivatives containing pyrazole ring was prepared and their cytotoxicity against different human cell lines, including breast (MCF-7), colon (HCT-116) liver (HEPG2) cell lines, as well as normal melanocyte HFB4 was evaluated. Two of these chalcone derivatives with different IC50 and chemical configuration were chosen for molecular studies in detail with MCF-7 cells. Our data indicated that the two compounds prohibit proliferation, angiogenesis, cell cycle progression and induce apoptosis of breast cancer cells. This inhibition is mediated by up regulation of tumor suppressor p53 associated with arrest in S-G2/M of cell cycle. This work provides a confirmation of antitumor activity of the novel chalcones and assists the development of new agents for cancer treatment.

The purpose of this work is to know the effect of flutamide and a novel synthetic steroid 3β-p-Iodobenzoyloxypregnan-4,16- diene-6,20-dione (IBP) on the levels of dopamine, 5-HIAA (5-hydroxyindole acetic acid), and some oxidative stress markers in animal model with Huntington disease. Thirty male Wistar rats divided in groups of 6 animals each were subjected to the following treatment: group A, 3-nitro propionic acid (3-NPA, as inducer of Huntington); group B, flutamide; group C, 3-NPA + flutamide; group D, IBP; and group E, 3-NPA + IBP. Treatment scheme for all groups were at 4 mg/kg/day administered intraperitoneally. The measurement of haemoglobin was carried out from blood while the concentrations of ATPase, 5α-reductase, reduced glutathione (GSH), calcium, H2O2, 5-HIAA, and dopamine were determined from brain and prostate tissues using validated methods. The results depicted a significant decrease of dopamine and GSH in cerebellum/Medulla oblongata of animals treated with IBP. The prostate gland of the same group of treatment also showed a significant decrease in the concentrations of TBARS, H2O2, and total ATPase. In hemispheres of groups D and E, dopamine, H2O2, and total ATPase decreased significantly while in prostate, hemispheres, and cerebellum/Medulla oblongata of groups B and C; calcium, 5α-reductase, ATPase, H2O2, and TBARS were found to witness a significant decrease. Results showed an antiandrogenic activity of flutamide, while the novel steroid IBP showed neuroprotective properties by changes on oxidative stress biomarkers as critical pathways leading to prostate and brain degeneration. Probably steroid homeostasis disequilibrium could have led to alterations in dopamine metabolism GSH in Huntington´s disease animal models.

Background: Oral cancer is the most common type of head and neck cancer and its high rate of mortality and morbidity is closely related to the processes of angiogenesis and tumor metastasis. The overexpression of the pro-angiogenic genes, HIF-1α and VEGF, and pro-metastatic gene, ROCK-1, are associated with unfavorable prognosis in oral carcinoma. Melatonin has oncostatic, antiangiogenic and antimetastatic properties in several types of neoplasms, although its relationship with oral cancer has been little explored. This study aims to analyze the expression of the genes HIF-1α, VEGF and ROCK-1 in cell lines of squamous cell carcinoma of the tongue, after treatment with melatonin. Methods: SCC9 and SCC25 cells were cultured and cell viability was assessed by MTT assay, after treatment with 100 μM of CoCl2 to induce hypoxia and with melatonin at different concentrations. The analysis of quantitative RT-PCR and the immunocytochemical analysis were performed to verify the action of melatonin under conditions of normoxia and hypoxia, on gene and protein expression of HIF-1α, VEGF and ROCK-1. Results: The MTT assay showed a decrease in cell viability in both cell lines, after the treatment with melatonin. The analysis of quantitative RT-PCR indicated an inhibition of the expression of the pro-angiogenic genes HIF-1α (P < 0.001) and VEGF (P < 0.001) under hypoxic conditions, and of the pro-metastatic gene ROCK-1 (P < 0.0001) in the cell line SCC9, after treatment with 1 mM of melatonin. In the immunocytochemical analysis, there was a positive correlation with gene expression data, validating the quantitative RT-PCR results for cell line SCC9. Treatment with melatonin did not demonstrate inhibition of the expression of genes HIF-1α, VEGF and ROCK-1 in line SCC25, which has different molecular characteristics and greater degree of malignancy when compared to the line SCC9. Conclusion: Melatonin affects cell viability in the SCC9 and SCC25 lines and inhibits the expression of the genes HIF-1α, VEGF and ROCK-1 in SCC9 line. Additional studies may confirm the potential therapeutic effect of melatonin in some subtypes of oral carcinoma.