Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 21, Issue 5, 2021

Cancer is considered one of the most threatening diseases worldwide. Although many therapeutic approaches have been developed and optimized for ameliorating patient’s conditions and life expectancy, however, it frequently remains an incurable pathology. Notably, conventional treatments may reveal inefficient in the presence of metastasis development, multidrug resistance and inability to achieve targeted drug delivery. In the last decades, nanomedicine has gained a prominent role, due to many properties ascribable to nanomaterials. It is worth mentioning their small size, their ability to be loaded with small drugs and bioactive molecules and the possibility to be functionalized for tumor targeting. Natural vehicles have been exploited, such as exosomes, and designed, such as liposomes. Biomimetic nanomaterials have been engineered, by modification with biological membrane coating. Several nanoparticles have already entered clinical trials and some liposomal formulations have been approved for therapeutic applications. In this review, natural and synthetic nanocarriers functionalized for actively targeting cancer cells will be described, focusing on their advantages with respect to conventional treatments. Recent innovations related to biomimetic nanoparticles camouflaged with membranes isolated from different types of cells will be reported, together with their promising applications. Finally, a short overview on the latest advances in carrier-free nanomaterials will be provided.

Background: Chalcones are structurally simple compounds that are easily accessible by synthetic methods. Heterocyclic chalcones have gained the interest of scientists due to their diverse biological activities. The anti-tumor activities of heterocyclic chalcones are especially remarkable and the growing number of publications dealing with this topic warrants an up-to-date compilation. Methods: Search for antitumor active heterocyclic chalcones was carried out using Pubmed and Scifinder as common web-based literature searching tools. Pertinent and current literature was covered from 2015/2016 to 2019. Chemical structures, biological activities and modes of action of anti-tumor active heterocyclic chalcones are summarized. Results: Simply prepared chalcones have emerged over the last years with promising antitumor activities. Among them, there are a considerable number of tubulin polymerization inhibitors. But there are also new chalcones targeting special enzymes such as histone deacetylases or with DNA-binding properties. Conclusion: This review provides a summary of recent heterocyclic chalcone derivatives with distinct antitumor activities.

Trans-resveratrol (RESV), pterostilbene, trans-piceid and trans-viniferins are bioactive stilbenes present in grapes and other plants. Several groups applied biotechnology to introduce their synthesis in plant crops. Biochemical interaction with enzymes, regulation of non-coding RNAs, and activation of signaling pathways and transcription factors are among the main effects described in literature. However, solubility in ethanol, short half-life, metabolism by gut bacteria, make the concentration responsible for the effects observed in cultured cells difficult to achieve. Derivatives obtained by synthesis, trans-resveratrol analogs and methoxylated stilbenes show to be more stable and allow the synthesis of bioactive compounds with higher bioavailability. However, changes in chemical structure may require testing for toxicity. Thus, the delivery of RESV and its natural analogs incorporated into liposomes or nanoparticles, is the best choice to ensure stability during administration and appropriate absorption. The application of RESV and its derivatives with anti-inflammatory and anticancer activity is presented with description of novel clinical trials.

Multiple Myeloma (MM) is the third most common and deadly hematological malignancy, which is characterized by a progressive monoclonal proliferation within the bone marrow. MM is cytogenetically heterogeneous with numerous genetic and epigenetic alterations, which lead to a wide spectrum of signaling pathways and cell cycle checkpoint aberrations. MM symptoms can be attributed to CRAB features (hyperCalcemia, Renal failure, Anemia, and Bone lesion), which profoundly affect both the Health-Related Quality of Life (HRQoL) and the life expectancy of patients. Despite all enhancement and improvement in therapeutic strategies, MM is almost incurable, and patients suffering from this disease eventually relapse. Curcumin is an active and non-toxic phenolic compound, isolated from the rhizome of Curcuma longa L. It has been widely studied and has a confirmed broad range of therapeutic properties, especially anti-cancer activity, and others, including anti-proliferation, anti-angiogenesis, antioxidant and anti-mutation activities. Curcumin induces apoptosis in cancerous cells and prevents Multidrug Resistance (MDR). Growing evidence concerning the therapeutic properties of curcumin caused a pharmacological impact on MM. It is confirmed that curcumin interferes with various signaling pathways and cell cycle checkpoints, and with oncogenes. In this paper, we summarized the anti- MM effects of curcumin.

Bladder cancer, a life-threatening serious disease, is responsible for thousands of cancer-associated deaths worldwide. Similar to other malignancies, standard treatments of bladder cancer, such as Chemoradiotherapy, are not efficient enough in the affected patients. It means that, according to recent reports in the case of life quality as well as the survival time of bladder cancer patients, there is a critical requirement for exploring effective treatments. Recently, numerous investigations have been carried out to search for appropriate complementary treatments or adjuvants for bladder cancer therapy. Curcumin, a phenolic component with a wide spectrum of biological activities, has recently been introduced as a potential anti-cancer agent. It has been shown that this agent exerts its therapeutic effects via targeting a wide range of cellular and molecular pathways involved in bladder cancer. Herein, the current data on curcumin therapy for bladder cancer are summarized.

Aims: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. Background: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. Objective: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. Methods: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. Results: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. Conclusion: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Background: Deoxypodophyllotoxin, isolated from the Traditional Chinese Medicine Anthriscus sylvestris, is well-known because of its significant anti-tumor activity with strong toxicity in vitro and in vivo. Objective: In this article, a series of deoxypodophyllotoxin derivatives were synthesized and their anti-tumor effectiveness was evaluated. Methods: The anti-tumor activity of deoxypodophyllotoxin derivatives was investigated by the MTT assay method. Apoptosis percentage was measured by flow cytometer analysis using Annexin-V-FITC. Results: The derivatives revealed obvious cytotoxicity in the MTT assay by decreasing the number of late cancer cells. The decrease of Bcl-2/Bax could be observed in MCF-7, HepG2, HT-29, and MG-63 using Annexin V-FITC. The ratio of Bcl-2/Bax in the administration group was decreased, which was determined by the ELISA kit. Conclusion: The derivatives of deoxypodophyllotoxin could induce apoptosis in tumor cell lines by influencing Bcl-2/Bax.

Background: Despite significant advances in therapeutic interventions, liver cancer is the leading cause of cancer mortality in the world. Potential phytochemicals have shown to be promising agents against many life-threatening diseases because of their low toxicity and potential effectiveness. Objective: The current study aims to conduct an in vitro investigation of the anticancer activity of Apricot Extract (AE) and Amygdalin Containing Fraction (ACF), additionally studying their therapeutic effects on DMBAinduced liver carcinogenesis mice model to highlight their related biochemical and molecular mechanisms. Methods and Results: Amygdalin was isolated from the seeds of P. armeniaca L. Male mice received AE or ACF, DMBA, DMBA+AE, DMBA+ACF, and vehicles. The oxidative stress and antioxidant markers, cell proliferation by flow cytometric analysis of Proliferating Cell Nuclear Antigen (PCNA) expression, angiogenesis marker (VEGF), inflammatory marker (TNF-α), apoptotic, anti-apoptotic and autophagy genes expression (caspase-3, Bcl-2, and Beclin-1) were investigated. AE and ACF were found to stimulate the apoptotic process by up-regulating caspase-3 expression and down-regulating Bcl-2 expression. They also reduced VEGF and PCNA levels and increased the antioxidant defense system. Moreover, AE and ACF treatments also inhibited HepG2 and EAC cell proliferation and up-regulated Beclin-1 expression. Conclusion: This study provides evidence that, in DMBA-induced hepatocarcinogenesis, the key proteins involved in the proliferation, angiogenesis, autophagy, and apoptosis are feasible molecular targets for hepatotherapeutic potential using AE and ACF.

Background and Purpose: Cancer is the primary cause of death in the world. Vanadium (IV) is a metal ion complex which has been proposed as a suitable candidate for cancer treatment. In this study, the interaction of the oxido-vanadium (IV) complex [VOL(bipy)] with salmon sperm DNA and Bovine Serum Albumin (BSA) was investigated through experimental and computational approaches. With the results of this experimental study, the mechanism and parameters related to the interaction of [VOL(bipy)] with DNA and BSA were determined. Materials and Methods: The kinetic interaction of DNA and BSA with [VOL(bipy)] was determined using absorption titration and fluorescence quenching, respectively. Moreover, the possible interactions were calculated by molecular docking prediction using the available software. Results: The binding constant (Kb) of the complex-DNA interaction was calculated to be 2.34×10⁴ M^-1, indicating a relatively strong interaction between the complex and DNA. It was found that the V(IV) complex interacted with DNA through the groove binding mode followed by partial intercalation into the DNA helix. The Kb values obtained for [VOL(bipy)]-BSA interaction were in the range of 1.07×10³-5.82×10⁴ M^-1. The V(IV) complex was found to prefer the domain I binding pocket of BSA with the ΔGb value of -7.52 kcal/mol. Conclusion: Both experimental and computational analyses confirmed the interaction of the vanadium complex with DNA and BSA. The moderate affinity of [VOL(bipy)] for BSA indicates that this protein is a good candidate for transferring the complex.

Background: T-LAK cell-Originated Protein Kinase (TOPK) belongs to the serine/threonine protein kinase family. It is highly expressed in RPMI7951 melanoma cells. Scutellarin (SCU) is an active ingredient extracted from Erigeron breviscapus (Vant.) Hand.–Mazz. Its main physiological functions are related to its anti-inflammatory and antitumour activities. Methods: The relationship between SCU and TOPK was assessed by molecular docking, an in vitro binding assay and an in vitro kinase assay. The effect of SCU on RPMI7951 cells was detected by MTS and soft agar assays. TOPK knockdown was induced by lentiviral infection. The TOPK downstream signalling pathway was detected by western blot and immunohistochemical analyses in vitro and in vivo. Results: SCU was found to directly bind with TOPK and inhibit TOPK activity in vitro. SCU inhibited the proliferation and colony formation of RPMI7951 cells in a dose-dependent manner. Silencing TOPK decreased the sensitivity of colon cancer cells to SCU. SCU inhibited the phosphorylation levels of Extracellular Regulated protein Kinases 1/2 (ERK1/2) and histone H3 in a time- and dose-dependent manner in RPMI7951 cells. In addition, SCU inhibited the growth of xenograft tumours of RPMI7951 cells and decreased the phosphorylation levels of extracellular regulated protein kinases 1/2 and histone H3 in vivo. Conclusion: The results showed that SCU exerts promising antitumour effects on human RPMI7951 cells by inhibiting the activity of TOPK.

Background: Cervical cancer is one of the most common gynaecological malignant tumors reported in women. Although a number of early screening and treatment options are available, mortality due to cervical cancer remains high. Nerium oleander L. is a potential medicinal plant that possesses a wide spectrum of pharmacological and physiological activities including anticancer activities. Objective: This study aims to evaluate the antiproliferative activity, inhibition of cell migration and cell cycle arrest by the chloroform extract of leaves of Nerium Oleander L. in HeLa cervical cancer cells. The chloroform extract of Catharanthus roseus which contains anti-cancer compounds, Vinblastin and Vincristin, was used as a positive control for this study. Methods: The chloroform extracts of Nerium oleander L. and Catharanthus roseus were prepared using the standard protocol. The cytotoxic effects were studied by MTT assay. Cell migration was studied by in vitro scratch assay. Analysis of the cell cycle was carried out by Propidium iodide staining and Flow Cytometry. The expression level of various proteins was evaluated by immunocytochemistry. Results: In this study, we showed that the leaf extract of Nerium oleander inhibited the growth of HeLa cervical cancer cells in culture and inhibited cell migration. Besides, it arrested the cell cycle at the G2/M phase. The Epidermal Growth Factor Receptor (EGFR) expression and phosphorylated p-Rb (Ser 780) level were significantly downregulated by leaf extract of Nerium oleander. Conclusion: The extract of Nerium oleander L. contains potential bioactive compounds that inhibit HeLa cell proliferation, cell migration and arrest cell cycle at the G2/M phase.

Background: Although film-forming hydrogels possess the advantages of both film and hydrogel dosage forms, certain limitations still remain. Objective: This study aims to investigate the use of film-forming hydrogels and the effects of nanocarriers on the sustained release of a poorly water-soluble drug, curcumin. Methods: The film-forming hydrogels contained either zein or polyvinylpyrrolidone as a film former, in addition to hydroxypropyl methylcellulose, oleic acid, ethanol and water. Curcumin was encapsulated in poly(lacticco- glycolic acid) and gelatine nanoparticles using a sonoprecipitation method. Free drug and drug-loaded nanoparticles were later dispersed into blank hydrogels to produce the film-forming nanogels. Results: The results suggested that the encapsulation of curcumin in nanoparticles could reduce the drug particle size to less than 200nm for easier diffusion and could shield curcumin from chemical interactions that limit its topical permeability. Curcumin was more compatible with gelatine nanoparticles than with poly(lactic-coglycolic acid) nanoparticles, and gelatine nanoparticles, in turn, were more compatible with zein than with polyvinylpyrrolidone film-forming nanogels. Therefore, gelatine nanoparticles in zein film-forming nanogels greatly elevated the permeability of curcumin by over five times that afforded by gelatine nanoparticles in polyvinylpyrrolidone film-forming nanogels. Conclusion: This research suggested that film-forming nanogel is a promising drug delivery system for both improved permeability and sustained topical diffusion of the extremely hydrophobic drug curcumin depending on the compatibility between the nanocarrier and the film-forming hydrogel.