Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 17, Issue 10, 2017

Background: Ingenol mebutate gel is a recent stirring weapon recommended for the treatment of multiple actinic keratoses (AKs) and field cancerization. This review brings a summary of recent data on the treatment of AKs with ingenol mebutate (IM) providing critical commentary with regard to drug's characteristics, drug's safety profile, treatment regimen, treatment outcome, patient compliance, AK recurrence, costeffectiveness and cost-utility, as well as guidelines for the management of the treatment of AK. Method: We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Reports on ingenol mebutate from U.S. Food and Drug Administration and European Medical Agency were also included. Results: Sixty-six papers were included in this review. We report current data on ingenol mebutate chemical properties, pharmacology, efficacy, safety, and tolerability, potential new indications in dermatology, costeffectiveness, and cost-utility analysis. Conclusion: Treatment of AKs is necessary in order to prevent possible transition to invasive SCC. Although the mechanism of action of ingenol mebutate is not fully elucidated, dual mechanism of action is presumed. Ingenol mebutate is an effective and cost-saving topical agent for the treatment of AK, especially multiple AKs and field cancerization, with acceptable safety profile. It may also have perspective in dermatology regarding the treatment of superficial BCC, Bowen disease, actinic cheilitis, and anogenital warts that has to be evaluated in clinical trials. Patients' adherence to recommended treatment regimen and auspicious safety profile make this drug attractive.

Background: Osteosarcoma (OS) is a common bone malignant tumor, which is the eighth leading form of pediatric cancer. Despite the modern chemotherapeutic development of OS, a number of patients with OS have a high risk of lung metastasis and local relapse after chemotherapy. Objective: This review study focused on the role of long non coding RNAs (lncRNAs) in OS progression, and presented update reports on OS treatment by targeting specific lncRNAs. Method: We have acquired information on OS and lncRNAs from scientific databases like google scholar, pubmed and scopus, and reviewed for this study. Results: The lncRNAs regulate a number of biological processes, and abnormal expression of lncRNAs could play role in many cancers and other human diseases. Interestingly, some lncRNAs can act as oncogenes, while some act as tumor suppressor genes. A number of studies revealed that targeting the specific lncRNAs by RNA interferance technology may provide a novel therapeutic strategy in the treatment of OS. Conclusion: LncRNAs could be a promising biomarker and might be a potential therapeutic target in OS patients.

Background: It has been postulated that colon cancer is the third cause of cancer death worldwide. Recently, colon-targeted drug delivery systems have been developed for improving systemic drug delivery and treatment of local colon associated diseases. Using such drug delivery systems increases the drug's effectiveness and results in reduced systemic side effects. Drug delivery systems formulated for the colon requires that the triggering of drug release mechanism is designed based on the colon’s physiological conditions. However, improving the site specificity and drug release kinetics of colon-targeted drug delivery systems is desired and is currently under active research. Objective: This review discusses colon cancer along with various colon-targeted drug delivery systems such as pro-drug formation, pH-sensitive polymers, hydrogels, time-dependent release systems, bio-adhesive and nanoparticle systems. The aim is to understand the effect of using colon-targeted drug delivery systems on therapeutic effectiveness of the drug by improving its degradation and bioavailability. Colon targeting holds a great promise as a therapeutic approach but it still requires more innovation. Conclusion: The distribution of the drugs in the colon suffers from problems related to the pH, retention time, micro-flora, and degrading enzymes of gastrointestinal tract. Moreover, these drug delivery systems are capable of overcoming some of the limitations in common targeting approaches. A precise assessment of such systems needs the use of various assaying protocols in order to characterize their traits and clarify their design rationales.

Recent advances in the treatment of pediatric tumors led to an improvement of survival in this population. As a result, many pediatric survivors experience long-term effects that impact their quality of life. Therefore, it is extremely important to identify new treatment approaches that may target the tumor minimizing the drug-related side effects. Over the past 10 years, remarkable advances in nanomedicine have provided several potential tools for cancer treatment. Recently, there has been a growing interest towards therapeutic nanocarriers in the pediatric field, since they represent a new strategy to enhance the drug efficacy and reduce the toxicity. Various nanoformulations have been developed to improve the targeting and the release of antitumor compound to cancer cells in pediatric tumors and clinical trials have been conducted or are ongoing. Exosomes are nanometer-sized vesicles that play a crucial role in mediating intercellular communication. Thanks to to their intrinsic cell targeting properties, stability in the circulation, and bio-compatibility, they are emerging as new promising vehicles both for drugs and biological therapeutics. Moreover, these nanovesicles are a reservoir of potential diagnostic and prognostic markers. In this review, we describe recent advances in the treatment of pediatric tumors through nanodelivery system with particular attention to neuroblastoma, soft-tissues/bone sarcomas and pediatric brain tumors. Furthermore, we explore the potential role of exosomes as an effective option of nanodelivery providing insights into their characteristics in pediatric tumors and their use in adult clinical trials.

Cellular immunotherapies such as CAR-T cell therapy and TCR-T cell therapy are relatively new, highly promising approaches for the treatment of cancer. In CAR-T cell therapy, a patient's T cells are engineered to express chimeric antigen receptors targeting tumor-associated cell surface antigens. In TCR-T cell therapy, the patient's T cells are engineered to express receptors targeting intracellular antigens. This report will summarize presentations from the recent CAR-TCR summit in Boston on September 13-16, 2016. These presentations were given by leaders in the field and many were divided into three streams: Discovery and Genetic T Cell Engineering; Translation and Clinical Development; and Manufacturing, Supply Chain and Commercialization. The report summarizes major pharmaceutical companies developing these novel therapies and provides challenges and perspectives for future therapeutic developments.

In a series of studies carried out over the last couple of years in various cell types, it was observed that the experimentally used Src family kinase inhibitors PP1 and PP2 and the clinically used Src/Abl inhibitors AZM475271 and dasatinib are potent inhibitors of TGF-β mediated cellular responses such as Smad and p38 mitogen-activated protein kinase phosphorylation, Smad-dependent transcriptional activation, growth inhibition, epithelial-mesenchymal transition (EMT), and cell motility. While for PP1/PP2 it was demonstrated that these agents directly inhibit the kinase activity of the TGF-β type I receptor activin receptor-like kinase 5, the mechanism of the anti-TGF-β effect of AZM475271 and dasatinib is less clear. In contrast, the anti-TGF-β effect of yet another Src/Abl inhibitor, bosutinib, is more variable with respect to the type of the TGF-β response and the cell type affected, and lacks a clear dose-dependency. In the light of their strong anti-activin receptor-like kinase 5 kinase effect, PP1 and PP2 should not be used when studying the role of c-Src as downstream mediators in TGF-β/activin receptor-like kinase 5 signaling. On the other hand, based upon in vitro findings, it is conceivable that part of the therapeutic effects of AZM475271 and dasatinib seen in preclinical and clinical studies with solid tumors was caused by inhibition of prometastatic TGF-β rather than Src signaling. If AZM475271 and dasatinib can indeed act as dual Src / TGF-β inhibitors in vivo, this may be beneficial for prevention of metastatic disease in more advanced tumor stages.

Background: Ferulenol, a sesquiterpene coumarin, was extracted from “Ferula vesceritensis” and possesses pro-oxidative and anticancer effects in different types of cancer. Objective: The objective of this study is to determine whether ferulenol has an anticancer effect by regulation the Bcl2 protein expression in lung cancer induced by benzo[a]pyrene in Wistar rats. Methods: Rats in group 1 have received, intraperitoneally, olive oil and considered as controls, animals of group 2 were treated with 100 mg/kg of benzo[a]pyrene intraperitoneally in order to induce lung cancer for 24 weeks, the 3rd groups of rats received the ferulenol 50 mg/kg intraperitoneally after 24 weeks of administration of benzo[a]pyrene and the last group, the rats were treated with ferulenol alone 50 mg/kg. Results: Treatment with ferulenol significantly increased the rate of lipid peroxidation and decrease enzymatic (CAT and GST) and non-enzymatic (GSH) anti-oxidants in benzo[a]pyrene induced lung cancer. Anticancer efficacy of ferulenol was evaluated by down-regulation of Bcl2 protein and up-regulation of Bax protein, Therefore, ferulenol can alter the functionality of lung mitochondria by increasing the production of superoxide anion and mitochondrial swelling. Conclusion: Together, our results depict that ferulenol can be used as pro-oxidant and chemotherapeutic agent against lung cancer.

Objective: The aim of the study wasto fabricate curcumin-loaded PLGA-PEG-Fe3O4 nanoparticles and comprise the effects of pure curcumin and curcumin-nanomagnetic encapsulated in PLGA-PEG on cell cytotoxicity and hTERT gene expression in A549 lung cancer cell line. Background: Lung cancer is the most common cancer in men and one of the four main cancers that occurs in women. Telomerase is active in more than 85% of various cancerous cells such as lung cancer while its activity is very low in normal cells. Strong evidences of antitumor effects of curcumin; such as the activation of apoptosis, inhibition of angiogenesis and prevention of metastasis, have been confirmed. However, extensive clinical application of this relatively efficacious agent in cancer therapy has been limited because of poor aqueous solubility, and consequently, minimal systemic bioavailability. Nanoparticle-based targeted drug delivery approach has the potential for rendering curcumin specifically at the favorite site using an external magnetic field. It can also improve availability and circumvent the pitfalls of poor solubility. Methods: Curcumin and Fe3O4 were encapsulated inside the PLGA-PEG co-polymer. Then, the curcumin loaded PLGA-PEG-Fe3O4 nanoparticles were characterized using SEM, FTIR and VSM. In the next step, the cytotoxic effect of different concentrations (0-120 µM) of free curcumin and equivalent doses of curcumin-loaded PLGA-PEG-Fe3O4 was assessed using MTT assay at 24-72 hours. Also, gene expression levels of hTERT were measured through Realtime PCR. Results: By encapsulation of curcumin-Fe3O4, cytotoxicity of the drug substantially increased for all concentrations. IC50 of pure curcumin and nano-encapsulated curcumin during 24, 48 and 72 hours was obtained as 50.5, 49.1 and 48.3 µM and 23.7, 13.6 and 7.3 µM, respectively. Moreover, nano-encapsulated curcumin showed time-dependent cytotoxic effect on A549 cell line during 24, 48, 72 hours in comparison to pure curcumin. In addition, the expression level of the hTERT was reduced with increasing concentrations in both pure and nano-encapsulated curcumin. Compared to pure form, nano-encapsulated curcumin caused further decline in the expression levels of the gene. Conclusion: Curcumin incorporating with Fe3O4 loaded into PLGA-PEG co-polymer, as an effective targeted carrier, can make a promising horizon in targeted lung cancer therapy.

Background: Apicidin, as an inhibitor of histone deacetylase, showed a wide range of antiproliferative activity against various cancer cell lines. Apicidin has also been reported to induce apotosis via Fas/Fas ligand. Yet few studies have been focused on mitochondrial pathway for its anti-tumor activity. Objective: In this study, we evaluated its involved mitochondrial mechanism against non-small cell lung cancer GLC-82 cells. Method: Apicidin was isolated from the mangrove endophtic fungi Fusarium sp. by solvent extraction and column chromatography. Its structure was elucidated by MS and NMR spectroscopic data, and comparison of those data with published data. Furthermore, anti-tumor activity and mitochondrial pathway of apicidin against GLC-82 cells were studied. Results: Apicidin was obtained from secondary metabolites of Fusarium sp., and it showed potent inhibitory activity against GLC-82 cells with the IC50 value of 6.94 ± 0.27 µM. Furthermore, apicidin suppressed proliferation and invasion, and induced apoptosis via mitochondrial pathway in GLC-82 cells, including loss of ΔΨm, release of cytochrome c from mitochondria, activation of caspase-9 and -3, and cleavage of poly-ADP-ribose polymerase. Conclusion: Apicidin, an inhibitor of histone deacetylase obtained from the mangrove endophytic fungi Fusarium sp., not only inhibited proliferation and invasion of GLC-82 cells, but also induced apoptosis via the mitochondrial pathway.

Objective: The present study aimed to explore the cytotoxic effect of ortho- and para-positional isomers of thiophene acetyl salicylic acid esters against cancer and normal cell lines. Method: Two new thiophene-2-acetic acid esters (2-((2-(thiophen-2-yl)acetyl)thio)benzoic acid and 4-((2-(thiophen-2- yl)acetyl)thio)benzoic acid) were synthesized and characterized by Elemental analysis, Fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance (NMR), 13C-NMR and High-resolution mass spectroscopy. The compounds were tested for their in vitro cytotoxic activity against A549 and Caco2 tumor cell lines and CCD- 19Lu and CCD 841 CoN normal cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,4,diphenyltetrazolium bromide assay. 2-((2-(thiophene-2-yl)acetyl)thio)benzoic acid showed a higher activity with (IC50 = 239.88µM/mL) compared with a reference drug nearly as active as cyclophosphamide (IC50 = 257.11 µM/mL) on Caco2 cell line. Apoptosis was observed by flow cytometric analysis on Caco2 cells. Result: Thus, positional isomerism is critical for the pharmacological properties of thiophene acetyl salicylic acid esters against colon cancer cell line compared with nonsmall cell lung cancer cell line. The ortho-isomer induced cell death and was much more potent than the para-isomer.

Background: Several pyrazolo[3,4-d]pyrimidine derivatives have been reported as anti-cancer agents via acting as EGFR inhibitors, mammalian target of rapamycin (mTOR) inhibitors, Src or dual Src/Abl inhibitors, glycogen synthase kinase-3b (GSK-3b) inhibitors or cyclin dependent kinase (CDK) inhibitors. Objective: A new series of hybrid pyrazolo[3,4-d]pyrimidine scaffold with a heteroaryl moiety as pyrazole, oxadiazole, triazole or phthalimide moiety (14a-f, 16, 17, 19, 20) was synthesized and biologically evaluated for the cytotoxicity against human liver cancer cell line (HEPG-2), human breast cancer cell line (MCF-7) and human colon cancer cell line (HCT-116). Results and Method: While the pyrazolo hybrid compounds (14a-f) showed good activity against HEPG-2, MCF- 7 and HCT-116 cell lines (IC50 = 3.65 – 39.98, 1.45 – 54.19 and 2.00 – 50.6 µM respectively) in comparison with doxorubicin (IC50 = 5.66, 2.60 and 8.48 µM respectively), the triazolo derivatives (17, 19) showed considerable potency (IC50 = 22.20 – 54.61, 14.98 – 88.78, and 10.79 – 53.40 µM respectively), the oxadiazolo hybrid compound (16, IC50 = 149.91, 115.89 and 110.07 µM respectively) and phthalimido hybrid compound (20, IC50 = 96.02, 131.19 and 120.36 µM respectively) showed low potency. The pyrazolo derivative (14d, IC50 = 3.65, 1.45 and 2.00 µM) was the most potent among all compounds against HEPG-2, MCF-7 and HCT-116 cell lines respectively. Also, the hybrid pyrazolo[3,4-d]pyrimidine derivatives were evaluated for their inhibitory activity to epidermal growth factor receptor tyrosine kinase (EGFR-TK) and they showed a good inhibitory activity (IC50 = 8.27 – 19.03 µM). With the exception of the pyrazolo derivative (14c, IC50 = 18.82 µM), the inhibitory activity against EGFR-TK was consistent with the in vitro cytotoxic activity against HEPG-2, MCF-7 and HCT-116 cell lines. Conclusion: The newly synthesized compounds showed good activity against HEPG-2, MCF-7 and HCT-116 cell lines in comparison with the reference drug doxorubicin.

Background: A DNA-RNA-lipoprotein complex, termed as virtosome, is released spontaneously from healthy human, other mammalian, avian, amphibian and plant cells in a regulated and energy-dependent manner. Studies on human and mouse lymphocytes, hepatocytes, NIH 3T3 cells and mouse tumour cell lines have shown that virtosomes may be acting as inter-cellular messengers. In particular, virtosomes from non-dividing cells blocked 3H-thymidine incorporation into DNA in tumour cell lines. Objective: Study of the effect of virtosomes on tumors “in vivo” and “in vitro”. Methods and Results: The present study shows in vitro effects of virtosomes isolated from rat liver, essentially nondividing cell populations, on cultures of healthy smooth muscle cells (SMC), human umbilical vein endothelial cells (HUVEC), human fibroblasts (h-fibroblasts) and mouse embryonic fibroblasts (NIH-3T3) together with two tumour cell lines, human Duke's type B colorectal adenocarcinoma cells (SW480) and human connective tissue fibrosarcoma cells (HT1080). Multiplication of all cell lines was inhibited by the liver virtosomal preparation even with various dilutions of the extract (100 - 0.5%). In an in vivo study, tumours were initiated by subcutaneous injection of 1.0 x 106 DHD/K12-PROb cells in 6 weeks old male BIDX rats. Visible tumours (<1cm) appeared after 3 weeks and lung metastases after 8 weeks (80%). Virtosomes introduced via a tail vein on tumour initiation resulted in a reduction in tumour size and number. Conclusion: Virtosomal preparation from a non-dividing cell population inhibited cell division, reduced tumour size and partially blocked metastasis.

Background: Thiourea derivatives bearing sulfonamide moiety are well known for their anticancer activity. Objective: The anticancer activity of the target compounds was studied, via inhibition of COX-2 enzyme. Method: A series of novel thioureas 5a-n, 8, quinazoline 6, benzo[g]quinazoline 7 and benzo[1,3] dioxole 10, bearing a sulfonamide moiety was synthesized from the starting compound N-(2,6-dimethoxypyrimidin-4-yl)-4- isothiocyanatobenzenesulfonamide 2. The target compounds were screened against HepG2, MCF-7, Caco-2, HCT-116, PC-3 cancer cell lines and VERO-B normal cell line. Results: Out of all the tested compounds, compound 5c showed a broad selective cytotoxicity against HepG2, MCF-7, Caco-2 and PC-3 cancer cells. Moreover, a sensitization assay was performed on Caco-2 cells, and compound 5c proved to act as a chemosensitizer for cisplatin on colon cancer (Caco-2) cells. The target compounds were further screened in vitro for their anti COX1/COX2 activity and investigated in vivo as antiinflammatory agents against carrageenan-induced rat paw oedema model. Conclusion: Compound 5g showed the most selective inhibitory activity against COX-2. While, compounds 5a, 6, 5m, 5n, 5g and 5i revealed significant anti-inflammatory effect as presented in carrageenan-induced oedema assay. Molecular docking of the tested compounds disclosed important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme.

Background: Although anticancer chemotherapeutics are available in markets, side effects related to the drugs in clinical use lead to researchers to investigate new drug candidates which are more safe, potent and selective than others. Chalcones are popular with their anticancer activities with the several reported mechanisms including inhibition of angiogenesis, inhibition of tubulin polymerization, and induction of apoptosis etc. Objective: This study was focused on to synthesize of 1-(2,4/2,6-difluorophenyl)-3-(2,3/2,4/2,5/3,4- dimethoxyphenyl)-2-propen-1-ones (1-8) and investigate their cytotoxic properties with possible mechanism of action. Method: The compounds were synthesized by Claisen-Schmidt condensation. The chemical structures were confirmed by 1H NMR, 13C NMR, DEPT, COSY, HMQC, HMBC, 19F NMR and HRMS. In vitro cytotoxic effects of the compounds against human tumour cell lines [gingival carcinoma (Ca9-22), oral squamous cell carcinoma (HSC-2)] and human normal oral cells [gingival fibroblasts (HGF), periodontal ligament fibroblasts (HPLF)] were evaluated via MTT test. Results: All compounds had higher cytotoxicity than reference compound 5-Fluorouracil (5-FU). The compounds 3-7 had higher potency selectivity expression values (PSE) than 5-FU and PSE values of the compounds were over 100. All chalcone derivatives seem good candidates for further studies according to very remarkable and high PSE values. Conclusion: It was clearly demonstrated that compound 7 can induce early apoptosis at a concentration of 10 µM and dose-dependent late apoptosis starting at 10 µM. Compound 7 induced cleavage of the apoptosis marker PARP. The results indicate that new chalcones reported here can promote apoptosis in human tumour cell lines.

Background: Targeted imaging and therapy (theranostics) is a promising approach for the simultaneous improvement of cancer diagnosis, prognosis and management. Therapeutic and imaging reagents are coupled to tumor-targeting molecules such as antibodies, providing a basis for truly personalized medicine. However, the development of antibody–drug conjugates with acceptable pharmaceutical properties is a complex process and several parameters must be optimized, such as the controlled conjugation method and the drug-to-antibody ratio. Objective: The major aim of this work is to address fundamental key challenges for the development of versatile technology platform for generating homogenous immunotheranostic reagent. Method: We conjugated the theranostics reagent IRDye700dx to a recombinant antibody fusion protein containing a self-labeling protein (SNAP-tag) which provides a unique reaction site. Results: The resulting conjugate was suitable for the imaging of cancer cells expressing the epidermal growth factor receptor and demonstrated potent phototherapeutic and imaging activities against them. Conclusion: Here, we describe a simple, rapid and robust site-directed labeling method that can be used to generate homogeneous immunoconjugate with defined pharmacological properties.

Background: The epigenetic regulation of genes in cancer could be targeted by inhibiting Histone deacetylase 6 (HDAC6), an enzyme involved in several types of cancer such as lymphoma, leukemia, ovarian cancer, etc. Objective: Through in silico methods, a set of Phenyl butyric acid derivatives with possible HDAC6 inhibitory activity were designed, rendering monophenylamides and biphenylamides using tubacin (HDAC6 selective inhibitor) as reference. Method: The target compounds were submitted to theoretical ADMET analyses and their binding properties on different HDAC6 conformers were evaluated through docking calculations. Results: These in silico studies allowed us to identify a compound named B-R2B. In order to have more information about the B-R2B binding recognition properties on HDAC6, the B-R2B-HDAC6 complex was submitted through 100 ns-long Molecular Dynamics (MD) simulation coupled to MMGBSA approach, revealing that B-R2B is located at the entrance of HDAC6 active pocket, blocking the passage of the substrate without reaching the HDAC6 binding site. Based on these results, B-R2B was synthesized, characterized and biologically tested. The HDAC6 fluorometric drug discovery kit Fluor-de-Lys (ENZO Life Sciences Inc.) was used to determine the HDAC6 human inhibitory activity (IC50 value) of B-R2B compound. In addition, B-R2B show IC50 values on cancer cell lines (HeLa; IC50 = 72.6 µM), acute myeloid leukemia (THP-1; IC50 = 16.5 µM), human mast leukemia (HMC; IC50 = 79.29 µM) and chronic myelogenous leukemia (Kasumi; IC50 = 101 µM). Conclusion: These results show that B-R2B is a HDAC6 inhibitor, specifically a non-competitive type in a similar way that tubacin does, according to MD simulations.