Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 17, Issue 12, 2017

Cancers have increased threat to human health due to the limited treatment efficacy of chemotherapy and radiotherapy with a series of toxicity and side effects; therefore, the development and utilization of natural products with potential preventive and therapeutic efficacy, and less toxicity and side effects will be beneficial to promote the health of cancer patients. In this article, the activity of ampelopsin as a natural flavonoid and its underlying molecular mechanisms for the prevention and treatments of hepatic carcinoma, breast cancer, prostate cancer and melanoma through inhibiting cell proliferation, accelerating apoptosis, inducing reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress, suppressing angiogenesis, invasion and metastasis, and synergizing the efficacy of other anti-cancer drugs have been summarized. This study will provide a reference for the development and utilization of other natural products.

Cancer cells do create hostile microenvironment (deprivation of nutrients, accumulation of acidity, anoxic habitat). Those cells are not only adapted to this sanctuary environment, blunting of immunity but also, grow, migrate to the distal area (metastasis) and communicate with each other in a unique population structure and organization too (clonal expansion). The adaptation requirements push those types of adaptable cells (cancer cells) to be primitive cells. The prevailing pharmacological approach in treating cancer is developing a chemotherapeutic agent that acts on rapidly proliferating cells that are stuck with normally growing epithelium and bone marrow too. The latter approach has been drafted to work on cellular target under the term of "targeted therapy" believing that each target represents Achilles Heels of cancer. In this article, we try to introduce a new concept of cancer pharmacology, by offering new off-label use of Doxycycline, which is characterized by selective toxicity, as potential anticancer agents. This notion is relying on the absence of taxonomic barriers.

Background: Rhein (1,8-dihydroxy-3-carboxyanthraquinone) is a monomer of anthraquinone derivatives mainly found in Polygonaceae plants such as Rhubarb, and Cuspidatum, widely used in the traditional Chinese medicine with many pharmacological activities, such as antitumor, anti-inflammatory and antifibrotic effects, and regulation of glucose and lipid metabolism. Objective: To conclude the role of Rhein in cancer control and its mechanisms for its futher deep research and potential clinical application. Method: All kinds of reports previously related to Rhein from PubMed datebase were collected, integrated and analyzed. Results: Rhein could control many cancer cells by regulating their proliferation and apoptosis, invasion and migration, especially intrinsic and extrinsic apoptosis pathways induced by Rhein plays the core role in cancer control. For good inhibitory role in NF-ΚB pathway, the Ras/Raf/MEK (MAPK)/ERK and PTEN/PI3K/AKT/mTOR pathways are other two key pathways regulated by Rhein with its role in antiphosphorylation of ERK, PI3K and AKT to control many cancers' development which frequently dysregulated in cancer, involved in the activation, proliferation, invasion, and migration of cancer cells. Conclusion: Rhein is a potential cancer treatment agent..

Background: Renal cell carcinoma (RCC) is responsible for 4% of all neoplasms in adults and 80% of all primary renal tumours. In the European Union, there are almost 84000 new cases and 35000 deaths each year due to RCC. In the last five decades, patients with localised RCC will develop recurrence of disease after nephrectomy in about 50% of cases. Considering the number of novel targeted therapies approved in the last years for the treatment of mRCC, there has been great interest to assess the efficacy of the same agents in the adjuvant setting. Objective: to provide a systematic review of literature on the available data to define whether adjuvant treatment plays a role in the management of RCC. Methods: A literature search using PubMed was carried out with no date restriction up to November 2016. A computerized search of the abstracts reported at ASCO and ESMO library, and www.clinicaltrial.gov was performed in order to identify relevant unpublished studies and ongoing trials. Results: the search strategy returned 908 entries: after the exclusion of 886 irrelevant publications, 22 studies were eligible for the systematic review. Conclusion: Currently, there is no robust evidence for the adjuvant treatment for patients with localized RCC at high risk of recurrence post-nephrectomy and often data are conflicting. It is necessary to identify new prognostic factors that might better predict the risk of relapse after surgery. The enrolment in adjuvant trials should be encouraged for the identification of selected patients who might benefit from adjuvant treatment.

Background: One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives. Objective and Method: Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene, and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible mechanisms. Results: Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar concentration (7.5-10 μM). Similarly, only compound 11 (a-c) had a significant activity in breast MCF7 cells at (4-7 μM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c) enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds. While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK) by up to 85%. The IC50 of derivative 11c against TK was at 173 nM. Conclusion: The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer and TK inhibitors.

Background: Berberine, a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids has drawn high attention for its several biological potencies. Objective: To furnish new rationalized derivatives based on berberine core which can deliver promising antioxidant and cytotoxic activities. Method: The N-Mannich base of an isoquinoline alkaloid, berberine, bearing substituted benzothiazole moieties was obtained. Novel synthesized analogues were in vitro screened for antioxidant efficacy toward 2,2-diphenyl- 1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) free radicals and in vitro cytotoxicity towards cervical cancer cell lines (HeLa and CaSki), an ovarian cancer cell line (SK-OV-3) and human renal cancer cell line (Caki-2). Cytotoxicity of the compounds toward normal cell lines was examined using the Madin-Darby canine kidney (MDCK) non-cancer cell line. Results: Analogues bearing a methoxy functional group (5e), acid functionality (5c), and a cyano group (5m) showed remarkable radical scavenging potential in DPPH and ABTS bioassays. Potent cytotoxicity exhibited by berberine against the HeLa cell line was attributable to the presence of a 2-aminobenzothaizole moiety (5a) and its 6-chloro congener (5g) on the berberine core, and the 6-cyano group (5m) on the benzothiazole ring revealed strong sensitivity for the CaSki cell line, whereas subjected scaffolds demonstrated diminished activity against the SK-OV-3 cell line. In addition, the compound with a 2-aminobenzothaizole moiety (5a), compound with methoxy functional group (5e) and compound with cyano group appeared with the most significant cytotoxicity effect in Caki-2 cell line. Their structures have been elucidated by FT-IR, 1H NMR, 13C NMR, and elemental analyses (CHN) essential research. Conclusion: N-Mannich bases of berberine were efficiently generated utilizing pharmacologically diverse substituted 2-aminobenzothiazole entities and final compounds were found remarkably active in antioxidant and cytotoxic assay. Hence, such types of compounds can be further studied or rationalized in future drug discovery studies.

Background: Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations. Objective: A preclinical toxicology study of paclitaxel biopolymer formulation (PBF) (paclitaxel-loaded poly(3- hydroxybutyrate) (PHB) microparticles) was done in order to assess its safety and to forecast side and toxic effects in a clinical study on patients. Method: PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The comprehensive study of cytotoxicity (on bone marrow stem cells), acute and chronic toxicity, allergenic and pyrogenic properties, histological investigation (in mice, rats and rabbits) of obtained PBF was carried out. Results: The acute toxicity study showed that PBF is much less toxic in equivalent PTX-content doses than PTX in conventional formulation when administered intraperitoneally to mice and rats. However, the chronic toxicity study showed that at intraperitoneal administration PBF has distinct cumulative properties and toxic effects that prevent PBF from clinical testing in current composition. Conclusion: Thus, the PBF as a prolong drug needs to correct its parameters for further drug formulation development.

Background: Excessive reactive species derived from oxygen and nitrogen leads to oxidative damage to tissue and organs. Capsaicin (CAP), a pungent component found in red pepper can prevent oxidative stress. Objective: The aim of the present work was to evaluate the protective effects of CAP loaded nano-emulsomes (EML) against the oxidative stress of rat livers induced through sodium fluoride (NaF). Method: EML was prepared by thin film hydration method that is development of thin lipid film followed by hydration and sonication. EML was characterized by Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD) techniques. EML was evaluated for drug entrapment, in vitro drug release, and in vivo study. Results: In vitro drug release study of optimized formulation showed that 50% of CAP was released within 50.21 min while 85% CAP was released in 227.4 min. Single oral dose of free CAP and CAP loaded EML were given to rats 2 hour after NaF administration. Membrane of hepatic cells was damaged by NaF and it was judged by the estimation of lipid peroxidation, reactive oxygen species (ROS), and catalase activity. The administration of CAP loaded EML 2 hr after NAF consumption showed significant decrease in ROS level compared to free CAP. EML containing CAP was more effective in comparison to free CAP in controlling the lipid peroxidation that is thiobarbituric acid substance augmentation in liver by the treatment of NaF. The administration of CAP loaded EML showed significant increase in catalase activity compared to free CAP administration. Conclusion: The results clearly demonstrated that CAP loaded EML may be accepted as an effective therapeutic formulation in preventing oxidative damage.

Background: Recently, we devoted to disclosing the antibacterial activities of enmein-type 6,7-seco-ent-kauranoid derivatives. Objective: Eleven new enmein-type diterpenoid derivatives with different substituents and drug-like properties were designed and synthesized. Method: The antimicrobial activities against E. coli, S. aureus, B. subtilis and M. albicans were disclosed. The antiproliferative activities against human cancer Bel-7402, K562, MGC-803 and CaEs-17 cells and non-cancerous L-02 cells were also measured by MTT method. Results: The results revealed that enmein-type diterpenoids showed more promising activities against tested gram-positive bacteria than gram-negative bacterium and fungus. Compound 9 with R of 2-quinolyl group exhibited the strongest antimicrobial activities with MIC values of 7.81 μg/ml and 0.98 μg/ml against S. aureus and B. subtilis, respectively. All the target derivatives exhibited superior cytotoxic activities to compounds 1 and 2 against tumor cells, and slight selectivity between cancerous cells and normal liver cells. Compound 12 with R of 3-(2-chloropyridyl) group and IC50 values of 0.7 μM, 0.9 μM, 0.8 μM and 2.0 μM agaist four tumor cells, respectively, was selected for further mechanism study in Bel-7402 cell line. Conclusion: Compound 12 could induce S phase cell cycle arrest and apoptosis at low concentrations via mitochondria-related pathways. The effects of compound 12 on some apoptosis related proteins showed that CDK2 was up regulated and ATM and cyclin A1 were down-regulated which confirmed the apoptosis and cell cycle effects.

Background: Cell migration is an essential process for survival and differentiation of mammalian cells. Numerous diseases are induced or influenced by inappropriate regulation of cell migration, which plays a key role in cancer cell metastasis. In fact, very few anti-metastasis drugs are available on the market. SphKs are enzymes that convert sphingosine to sphingosine-1-phosphate (S1P) and are known to control various cellular functions, including migration of cells. In human, SphK2 is known to promote apoptosis, suppresses cell growth, and controls cell migration; in addition, the specific ablation of SphK2 activity was reported to inhibit cancer cell metastasis. Objective: The previously identified SG12 and SG14 are synthetic analogs of sphingoid and can specifically inhibit the functions of SphK2. We investigated the effects of the SphK2 specific inhibitors on the migratory behavior of cells. Method: We investigated how SG12 and SG14 affect cell migration by monitoring both cumulative and individual cell migration behavior using HeLa cells. Results: SG12 and SG14 mutually showed stronger inhibitory effects with less cytotoxicity compared with a general SphK inhibitor, N,N-dimethylsphingosine (DMS). The mechanistic aspects of specific SphK2 inhibition were studied by examining actin filamentation and the expression levels of motility-related genes. Conclusion: The data revealed that SG12 and SG14 resemble DMS in decreasing overall cell motility, but differ in that they differentially affect motility parameters and motility-related signal transduction pathways and therefore actin polymerization, which are not altered by DMS. Our findings show that SphK2 inhibitors are putative candidates for anti-metastatic drugs.

Background: HMGB1 (High Mobility Group Box-1) is a very versatile highly abundant architectural protein that plays multiple roles in human health and diseases. Under physiological condition it serves as an amazing assortment of roles in different compartments of cell. The reported high expression of HMGB1 in almost all types of human cancers and inflammatory diseases makes it a critical molecular therapeutic target. Objective: In the present study, we have mobilized a proximal twenty one base pair nucleotide (21RY) which is in the promoter region (-55 to-75) of hmgb1 gene and targeted it with triplex forming oligonucleotide (TFO) in combination with two widely used chemotherapeutic drugs, actinomycin (ACT) and adriamycin (ADM). Method: The interaction of actinomycin and adriamycin to 21R*R•Y DNA triplex was studied using UV melting profiles, CD spectroscopy, spectrofluorimetry and Isothermal titration calorimetry. The 21R*R•Y formation was confirmed from biphasic thermal melting profiles, continuous variation method, analysis of CD marker band and thermodynamic parameters. Results: The binding of ADM and ACT to 21R*R•Y was characterized by hypochromic and bathochromic shift in their respective absorption spectrum, quenching (ADM) and enhanced fluorescence (ACT) of steady-state fluorescence intensity, perturbation in the circular dichroic spectrum and change in thermal melting temperatures. The ITC profile and Scatchard plot analysis indicate non-cooperative and higher binding affinity of these drugs to 21R*R•Y compared to their corresponding duplexes. Conclusion: Therefore, combining these chemotherapeutic drugs with triplex forming oligonucleotide may offer new diagnostic and therapeutic options in targeting a gene of interest more specifically with fewer side effects. This study shows that ACT and ADM effectively recognize 21R*R•Y triplex DNA formed on the hmgb1 promoter region.

Background: Phenolic compounds are known for their cytotoxic properties against cancer cells despite their still unclear general mechanism of action. Herein is reported the evaluation of the cytotoxic effects of on human osteosarcoma cells of nine phenol derivatives against osteosarcoma cells, and some insights on their mechanism. Method and Results: The cytotoxicity was characterized by cell viability, scratch assay, cellular DNA content measurement, Annexin V apoptosis, mitochondrial calcium and caspase 3/7 assays. The study shows that out of the nine compounds used in this study, a tetrahydroquinoline derivative, 2-((1,2,3,4-tetrahydroquinolin-1-yl)(4- methoxyphenyl)methyl) phenol, was found to exhibit strong inhibitory response with IC50 of 50.5 ± 3.8 μM, and therefore can be a potential chemotherapeutic agent. Further experiments revealed that this compound induces cell death by apoptosis and also act as a migration inhibitor. Analysis of the mitochondrial calcium following treatment with the compound on U2OS cells showed a significant reduction in the level of mitochondrial calcium concentration suggesting a mitochondrial calcium-independent mechanism in triggering apoptosis. Treatment of HEK293 cells with the compound confirmed the cytotoxic effects of the compound, however, an increase in the level of mitochondrial calcium was observed. Moreover, the caspase 3/7 mediated cell death was also observed in both cell types. Conclusion: Overall, the study suggests that the derivatives of this compound can be used for development of new therapeutics for osteosarcoma and other cancers.

Background: Ovarian cancer is most lethal among all gynecologic malignancies. Paclitaxel (PTX) is well used chemotherapeutic regimen for cancer control; however its undesired toxicity has been a matter of concern for clinicians. Here, we used the graphene oxide coated nanotised apigenin (GO-NA) to enhance the efficacy of paclitaxel. Objective: The combined use of paclitaxel (PTX) and nanotised apigenin (NA) may reduce the PTX dose and increase the efficacy. Methods: GO and GO-Apigenin was prepared by modified Hummers method and the nanoparticles were characterized by dynamic light scattering and transmission electron microscopy. SKOV-3 cells were treated by DMSO, Group I (Control)-McCoy's 5A Medium, Group II-Paclitaxel (5nM), Group III- Nanotised Apigenin (GO-NA-10μM), Group IV- Paclitaxel (5nM) + GO-NA (10μM). Cell viability and IC-50 value were determined by MTT assay, synergism by Compusyn software, ROS by DCFH-DA assay, SOD activity by kit and MMP were examined by JC-1 and mitotracker/DAPI staining, cell cycle by flow cytometry, mRNA and protein level by Real Time-PCR and Western blot respectively Results: Results showed that GO-NA-PTX enhanced the anti-proliferative effect in synergistic manner as compare to GO-NA and PTX alone. GO-NA-PTX significantly suppressed the SOD activity, promotes the ROS accumulation, mitochondrial depolarization, DNA integrity and cell cycle arrest collectively accord the apoptosis. Results of immunocytochemistry, RT-PCR and western blot showed up-regulation of caspase-3, Bax, and down-regulation of Bcl-2. Conclusion: The combination of PTX with GO-NA produces synergistic effects in SKOV-3 cells via the modulation of pro and anti-apoptotic gene and may reduce side effects of PTX.