Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 19, Issue 13, 2019

The spread of metastatic cancer cell is the main cause of death worldwide. Cellular and molecular basis of the action of phytochemicals in the modulation of metastatic cancer highlights the importance of fruits and vegetables. Quercetin is a natural bioflavonoid present in fruits, vegetables, seeds, berries, and tea. The cancer-preventive activity of quercetin is well documented due to its anti-inflammatory, anti-proliferative and anti-angiogenic activities. However, poor water solubility and delivery, chemical instability, short half-life, and low-bioavailability of quercetin limit its clinical application in cancer chemoprevention. A better understanding of the molecular mechanism of controlled and regulated drug delivery is essential for the development of novel and effective therapies. To overcome the limitations of accessibility by quercetin, it can be delivered as nanoconjugated quercetin. Nanoconjugated quercetin has attracted much attention due to its controlled drug release, long retention in tumor, enhanced anticancer potential, and promising clinical application. The pharmacological effect of quercetin conjugated nanoparticles typically depends on drug carriers used such as liposomes, silver nanoparticles, silica nanoparticles, PLGA (Poly lactic-co-glycolic acid), PLA (poly(D,L-lactic acid)) nanoparticles, polymeric micelles, chitosan nanoparticles, etc. In this review, we described various delivery systems of nanoconjugated quercetin like liposomes, silver nanoparticles, PLGA (Poly lactic-co-glycolic acid), and polymeric micelles including DOX conjugated micelles, metal conjugated micelles, nucleic acid conjugated micelles, and antibody-conjugated micelles on in vitro and in vivo tumor models; as well as validated their potential as promising onco-therapeutic agents in light of recent updates.

Background: In the last decade, many new avenues of cancer treatment have opened up but the costs of treatment have sky-rocketed too. Hence, screening of indigenously available plant and animal resources for anti-carcinogenic potential is an important branch of anticancer research. The effort has been made through this comprehensive review to highlight the recent developments of anticancer therapies using different parts of papaya plant extract. Methods: In search of the naturally existing animals and plants for anticarcinogenic potential, papaya plant has been exploited by the scientist working in this research field. A widespread literature search was performed for writing this review. Results: Different constituents of Carica papaya responsible for anticancer activities have been discussed. Papaya extract for the treatment of breast, liver, blood, pancreas, skin, prostate, and colon cancer have also been reported. Finally, the various formulation approach using Carica papaya extract have been highlighted. Conclusion: The information provided in this review might be useful for researchers in designing of novel formulation of Carica papaya extract for the treatment of cancer.

Background: Several studies have revealed that abnormal activation of Notch signaling is closely related with the development and progression of prostate cancer. Although there are numerous therapeutic strategies, a more effective modality with least side effects is urgently required for the treatment of prostate cancer. Carvacrol is a monoterpenoid phenol and majorly present in the essential oils of Lamiaceae family plants. Many previous reports have shown various biological activities of carvacrol like antioxidant, antiinflammatory and anticancer properties. Recently, we have shown potent anticancer property of carvacrol against prostate cancer cell line DU145. In the current study, we report the chemopreventive and therapeutic potential of carvacrol against another prostate cancer cell line PC-3 with its detailed mechanism of action. Methods: To determine the effect of the carvacrol on prostate cancer cells, the cell viability was estimated by MTT assay and cell death was estimated by LDH release assay. The apoptotic assay was performed by DAPI staining and FITC-Annexin V assay. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Cell cycle analysis was performed by flow cytometry. Gene expression analysis was performed by quantitative real time PCR. Results: Our results suggested that the carvacrol treatment significantly reduced the cell viability of PC-3 cells in a dose- and time-dependent manner. The antiproliferative action of carvacrol was correlated with apoptosis which was confirmed by nuclear condensation, FITC-Annexin V assay, modulation in expression of Bax, Bcl-2 and caspase activation. The mechanistic insight into carvacrol-induced apoptosis leads to finding of elevated level of Reactive Oxygen Species (ROS) and mitochondrial membrane potential disruption. Cell cycle analysis revealed that carvacrol prevented cell cycle in G0/G1 that was associated with decline in expression of cyclin D1 and Cyclin-Dependent Kinase 4 (CDK4) and augmented expression of CDK inhibitor p21. Having been said the role of hyperactivation of Notch signaling in prostate cancer, we also deciphered that carvacrol could inhibit Notch signaling in PC-3 cells via downregulation of Notch-1, and Jagged-1. Conclusion: Thus, our previous and current findings have established the strong potential of carvacrol as a chemopreventive agent against androgen-independent human prostate cancer cells.

Background: Based on recent studies, new therapeutic strategies have been developed for cancer treatment using microRNAs (miRNAs). With this view, miRNAs manipulating techniques can be considered as novel therapeutic prospects for cancer treatment. In this study, we evaluated the expression of miR-4301 in human lung cancer cell lines and investigated its potential role in cell proliferation and tumor suppression on Non-Small Cell Lung Cancer (NSCLC) cells. Methods: We used quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) to examine the level of miR- 4301 expression in human lung cancer cell lines (A549, QU-DB) and non-malignant lung epithelial cells (HFLF-PI5). Then, we investigated the effect of miR-4301 by transfecting it into these cell lines and probing for cancer cell viability and apoptosis using the MTT assay, flow cytometry and immunofluorescence staining. Results: Our results showed that the expression level of miR-4301 was significantly reduced in human lung cancer cell lines (P<0.001). When miR-4301 was transfected in lung cancer cells, their cell proliferation was suppressed and apoptosis induced. This decline in cell survival was confirmed by the MTT assay. Transfection of miR-4301 caused an increase in early and late apoptotic cells in all lung cancer cell lines tested. Conclusions: Our findings show that miR-4301 may act as a lung cancer suppressor through targeting of proteins involved in cell proliferation and survival. For this reason, targeting miR-4301 may provide a new strategy for the diagnosis and treatment of patients with this deadly disease. This article is protected by copyright. All rights reserved.

Background: Niclosamide is an FDA-approved and old anti-helminthic drug used to treat parasitic infections. Recent studies have shown that niclosamide has broad anti-tumor effects relevant to the treatment of cancer. However, this drug has a low aqueous solubility hindering its systemic use. Herein, we report the preparation and characterization of niclosamide nanoliposomes and their in vivo anti-tumor effects. Methods: Nanoliposomes were prepared using thin-film method and the drug was encapsulated with a remote loading method. The nanoliposomes were investigated by the observation of morphology, analysis of particle size and zeta potential. Additionally, qualitative and quantitative analyses were performed using HPLC. We assessed the in vitro cytotoxicity of the nanoliposomal niclosamide on B16F10 melanoma cells. Inhibition of tumor growth was investigated in C57BL/6 mice bearing B16F0 melanoma cancer. Results: Analytical results indicated that the nanoliposomal system is a homogeneous and stable colloidal dispersion of niclosamide particles. Atomic force microscopy images and particle size analysis revealed that all niclosamide particles had a spherical shape with a diameter of approximately 108nm. According to in vitro and in vivo studies, nanoliposomal niclosamide exhibited a better anti-tumor activity against B16F10 melanoma tumor compared with free niclosamide. Conclusion: Nanoliposomal encapsulation enhanced the aqueous solubility of niclosamide and improved its anti-tumor properties.

Background: There is some evidence that Benign Prostatic Hyperplasia (BPH) may increase the risk of developing prostate cancer, so conducting research on effective BPH inhibitors is important. Objective: This research studied the inhibitory effect of Iodized Serum Milk Protein (ISMP) on BPH in rats. ISMP is a concentrate of lactic protein containing 2.2% iodine. Methods: Male Wistar rats, aged 18 months, were used. In the intact control group, sunflower oil was administered intragastrically by gavage. In 36 rats, BPH was induced by surgical castration, followed by subcutaneous injections of prolonged testosterone - omnadren, 25mg/kg every other day (7 administrations). One group of rats served as BPH-control. ISMP and finasteride (positive control), dissolved in sunflower oil, were administered to rats intragastrically daily at a dose of 200μg/kg and 5mg/kg, respectively, for 4 weeks starting immediately after castration. Results: ISMP inhibited the development of BPH in rats, significantly reducing the mass of the prostate and its parts (except for the anterior lobes) by 1.1-1.3 times and the prostatic index (the ratio of prostate weight to the body weight) - by 1.3-1.4 times. Finasteride inhibited the development of BPH, and its activity was higher (by 1.1-1.3 times) than in ISMP. Histological analysis of the prostate showed fewer pronounced morphological hyperplasia signs in animals treated with ISMP or finasteride. Conclusion: The iodine-containing preparation ISMP has the ability to inhibit the development of BPH in rats although its activity is somewhat lower than that of finasteride.

Background: Ginsenoside Rh2 (Rh2), which is extracted from ginseng, exerts antitumor activity. Here we would like to study the role of Rh2 on hypoxia-induced migration in lung adenocarcinoma. Methods: Lung adenocarcinoma A549 and H1299 cells were cultured in 1% O2 condition to mimic the hypoxic tumor microenvironment. The migrations of cancer cells were measured by transwell assay and scratch assay. Results: Rh2 could inhibit hypoxia-induced A549 and H1299 cell migration via increase of mir-491 expression. Further, mir-491 antisense oligonucleotide could repress hypoxia-induced migration and the expression of matrix metalloproteinase (MMP)-9 expression in Rh2-treated A549 cells. Conclusion: These findings suggest that Rh2 exerts anti-metastasis activity in the hypoxic tumor microenvironment in lung adenocarcinoma cells via mir-491.

Background: Aberrant and proliferative expression of the oncogene BCR-ABL in bone marrow cells is one of the prime causes of Chronic Myeloid Leukemia (CML). It has been established that the tyrosine kinase domain of the BCR-ABL protein is a potential therapeutic target for the treatment of CML. Although the first and second line inhibitors against the enzyme are available, recent studies have indicated that monotherapeutic resistance has become a great challenge. Objective: In recent studies, the dual inhibition of BCR-ABL by Nilotinib and Asciminib has been shown to overcome drug resistance. This prompted us to investigate the dynamics behind this novel drug combination. Methods: By the utilization of a wide range of computational tools, we defined and compared BCR-ABL’s structural and dynamic characteristics when bound as a dual inhibitor system. Results: Conformational ensemble analysis presented a sustained inactive protein, as the activation loop, inclusive of the characteristic Tyr257, remained in an open position due to the unassailable binding of Asciminib at the allosteric site. Nilotinib also indicated stronger binding at the catalytic site in the presence of Asciminib, thus exposing new avenues in treating Nilotinib-resistance. This was in accordance with intermolecular hydrogen bond interactions with key binding site residues GLU399, Asn259 and Thr252. Conclusion: The investigations carried out in this study gave rise to new possibilities in the treatment of resistance in CML, as well as assisting in the design of novel and selective inhibitors as dual anti-cancer drugs.

Aims: This study was designed to investigate the phytochemical profile and the cytotoxic activities of the eco-friendly extracts of olive leaves from Chemlali cultivar. Materials and Methods: The Phenolic composition of olive leaves extracts, the antioxidant activity and the cytotoxic effects against MCF-7 and HepG2 cells were determined. Results: Olive leaves extracts showed relevant total polyphenols contents. Oleuropein was the major detected phenolic compound reaching a concentration of 16.9 mg/ml. The antioxidant potential of the studied extracts varied from 23.7 to 46.5mM Trolox equivalents as revealed by DPPH and ABTS assays. Cytotoxicity experiments showed similar trends for both HepG2 and MCF-7 cells with the infusion extract being the most active. Conclusion: This study denotes that olive leaves may have great potential as endless bioresource of valuable bioactive compounds which may have a wide application.

Background: Cancer is the second leading cause of death globally. Hydrazone and hydrazone derivatives have high activity, and for this reason, these compound are greatly used by researchers to synthesize new anti-cancer drug. The aim of this research work is to synthesize novel anticancer agents. Methods: New hydrazone derivatives were synthesized via a reaction between 3-formylphenyl methyl carbonate and benzhydrazide, 4-methylbenzoic hydrazide, 4-tert-butylbenzoic hydrazide, 4-nitrobenzoic hydrazide and 3- methoxybenzoic hydrazide, and were successfully characterized using elemental analysis, 1H-NMR, 13C-NMR, FT-IR and LC-MS techniques. The synthesized compounds were evaluated for their antimicrobial (some grampositive and -negative bacteria, filamentous fungi and yeasts), anti-proliferative (T47D and HCC1428-breast cancer cells) and anti-angiogenic (HUVEC-endothelial cells) activities. The anti-proliferative activities of the hydrazone compounds R1-R5 were studied on these cell lines by MTT assay. The anti-angiogenic potential of the compounds was determined by the endothelial tube formation assay. To identify structural features related to the anti-proliferative activity of these compounds, 2D-QSAR was performed. Result: The results indicated that compound R3 exhibited strong anti-angiogenic and anti-proliferative activity on breast cancer cell lines and healthy cell lines. Also, this compound; possessing a tertiary butyl moiety on the hydrazine, exhibited the highest inhibitory effect against all tested microorganisms; in particular, it inhibited Candida albicans at a lower concentration than ketoconazole. Among the investigated compounds, those bearing methyl, tertiary butyl (compound R2, R3) and methoxy (compound R5) moiety were found to be more successful anticandidal derivatives than standard antifungal antibiotics. The QSAR analysis suggested that the tumor specificity of the hydrazone correlated with their molecular weight, lipophilicity, molar refractivity, water solubility, DipolHybrid:(MOPAC) and ExchangeEnergy:(MOPAC). Absorption, Distribution, Metabolism and Elimination (ADME) analysis of the hydrazone compounds showed that they have favorable pharmacokinetic and drug-likeness properties. The ADME results clarify that R3 is the best compound in terms of pharmacokinetic properties. In contrast to other compounds; target prediction analysis of the compound R3 showed inhibitory activity on estrogen-related receptor alpha transcription factor (ESRRA). The target prediction analysis was supported by molinspiration bioactivity score. Conclusion: The R3 compound is considered to be an important candidate for future studies with its suitability for the Lipinski’s rule of five for drug-likeness, and effective in vitro and in silico results.