Anti-Cancer Agents in Medicinal Chemistry - Volume 20, Issue 16, 2020

Background: Although curcumin has been demonstrated to be beneficial in treating various diseases, its low solubility, chemical stability and bioavailability limit its application, especially in cancer therapy. Methods: Solid dispersions have been utilized in the last few decades to improve the bioavailability and stability of curcumin. Results: However, there is a lack of summaries and classifications of the methods for preparing curcumin with this technology. The current review aims to overview the strategies used to develop solid dispersions containing curcumin for improving drug delivery. The classification of techniques for creating solid dispersions for curcumin was summarized, including systems for protecting curcumin degradation despite its chemical stability. The applications of advanced nanotechnologies in recent studies of solid dispersions were also discussed to explain the roles of nanoparticles in formulations. Conclusion: This overview of recent developments in formulating solid dispersions for improving curcumin bioavailability will contribute to future studies of curcumin for clinical development.

MicroRNAs (miRNAs) are short, non-coding RNA molecules that regulate gene expression by translational repression or deregulation of messenger RNAs. Accumulating evidence suggests that miRNAs play various roles in the development and progression of lung cancers. Although their precise roles in targeted cancer therapy are currently unclear, miRNAs have been shown to affect the sensitivity of tumors to anticancer drugs. A large number of recent studies have demonstrated that some anticancer drugs exerted antitumor activities by affecting the expression of miRNAs and their targeted genes. These studies have elucidated the specific biological mechanism of drugs in tumor suppression, which provides a new idea or basis for their clinical application. In this review, we summarized the therapeutic mechanisms of drugs in lung cancer therapy through their effects on miRNAs and their targeted genes, which highlights the roles of miRNAs as targets in lung cancer therapy.

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

Development in the field of bio-inorganic chemistry increased the interest in Schiff base and its complexes due to its biological importance in many fields, including anticancer activity. Discovery of the antitumor activity of Schiff base and its complexes against various tumor cell lines fascinates the researchers to develop new anticancer drugs without any side effects. Thus, the present review focuses on the anticancer activity of Schiff bases and their metal complexes.

Objective: Polydopamine coated iron oxide nanoparticles (Fe3O4@PDA NPs) were synthesized, characterized, and their MR imaging contrast agents and photothermal potency were evaluated on melanoma (B16-F10 and A-375) cells and normal skin cells. To this end, MTT assay, Fe concentration, and MR imaging of both coated and uncoated NPs were assessed in C57BL/6 mice. Methods: Fe3O4 nanoparticles were synthesized using co-precipitation, and coated with polydopamine. The cytotoxicity of Fe3O4 and Fe3O4@PDA NPs on melanoma cells, with different concentrations, were obtained using MTT assay. MR images and Fe concentrations of nanoprobe and nanoparticles were evaluated under in vivo conditions. Results: Findings indicated that uncoated Fe3O4 showed the highest toxicity in animal (B16-F10) cells at 450μg/ml after 72h, while the highest toxicity in human (A-375) cells were observed at 350μg/ml. These nanoparticles did not reveal any cytotoxicity to normal skin cells, despite having some toxicity features in A-375 cells. MR image signals in the tumor were low compared with other tissues. The iron concentration in the tumor was higher than that of other organs. Conclusion: It is concluded that the cytotoxicity of Fe3O4@PDA was found to be significantly lower than uncoated nanoparticles (p <0.001), which allows some positive effects on reducing toxicity. The prepared nanoprobe may be used as a contrast agent in MR imaging.

Background: Previous studies reported the inevitable destructive effects of radiotherapy on normal adjacent cells. Ascorbic Acid (AA) has been proposed as an effective anti-cancer agent with no obvious effects on normal cells. Objective: The effects of Ascorbic acid in combination with radiotherapy on human pancreatic carcinoma cell line were studied. Methods: The human pancreatic cancer cells were cultured and divided into four groups: control group (A) without any treatment, group B that received 2Gy radiotherapy alone, group C that was treated with 4mM AA alone, and group D that was co-treated with AA and radiotherapy. Cell viability, DNA fragmentation, expression of apoptotic genes, and Reactive Oxygen Species (ROS) production were determined in treated cells. Results: There was a noticeable decrease in cell viability after treatment with AA (and/or) radiotherapy. All treated groups showed elevated ROS production, Bax/Bcl2 expression, DNA fragmentation, and cytotoxycity compared with the control group. Cells under combination therapy showed the most cytotoxicity. Conclusion: The results suggest that AA at a dose of 4mmol/l may be used as an effective radio-sensitizing agent in pancreatic cancer cell line.

Background and Purpose: O-GlcNAcylation is a significant protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc) for intracellular signaling. Elevated O-GlcNAcylation contributes to cell proliferation, cell migration, cell apoptosis and signal transduction in various cancers. However, the expression level and functional role of O-GlcNAcylation in Hypopharyngeal Squamous Cell Carcinoma (HSCC) is not clearly elucidated. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master transcriptional factor that has been found to be aberrantly activated in HSCC. Here, we provide a molecular rationale between O-GlcNAcylation and Nrf2 in HSCC patients. Methods: The protein levels of O-GlcNAcylation and Nrf2 in HSCC tissues were detected by immunohistochemistry technique and western blot analysis. Then, O128;GlcNAcylation knockdown HSCC cells were applied in this study. Cell proliferation was detected by CCK8, colony-forming analysis, and cell cycle assays. Cell migration and invasion ability was evaluated by transwell assays. Cell apoptosis was measured by TUNEL analysis. Results: O-GlcNAcylation was obviously up-regulated in HSCC tissues, which correlated with tumor size and lymph node metastasis. In addition, the protein level of Nrf2 was found to positively correlate with the expression of O-GlcNAcylation both in vivo and in vitro. Knockdown of O-GlcNAcylation significantly inhibited HSCC cell growth, suppressed cell migration, and promoted cell apoptosis, whereas overexpression of Nrf2 reversed these phenotypes. Mechanismly, the upregulation of O-GlcNAcylation promoted the phosphorylation of Akt, leading to the stabilization of Nrf2; this could be attenuated by inhibition of the PI3K/Akt signaling pathway. Conclusion: Here, we provide a molecular association between O-GlcNAcylation and Nrf2 in HSCC patients, thus providing valuable therapeutic targets for the disease.

Background: The high mobility group box 1 (hmgb1) is one of the frequently over-expressed genes whose aberrant expression is reported in a number of human cancers. Various strategies are underway to inhibit hmgb1 expression in cancer cells having considerable therapeutic value. Objective: The present work involves selective transcriptional inhibition of the hmgb1 gene using selective DNA triplex structure-based gene technology. Here, the promoter region of the hmgb1 gene at position (-183 to -165) from the transcription start site as a target was selected using bioinformatic tools. Methods: The DNA triplex formation by the DNA of the target gene and TFO was confirmed using UV absorption spectroscopy, Circular Dichroism, and Isothermal Calorimetry. Results: Treatment of HepG2 cell with specific Triplex-forming Oligonucleotide significantly downregulated HMGB1 expression level at mRNA and protein levels by 50%, while the classical anticancer drugs, actinomycin/ adriamycin as positive controls showed 65% and the combination of TFO and drug decreased by 70%. The anti-proliferative effects of TFO correlated well with the fact of accumulation of cells in the Go phase and apoptotic cell death. Further, the binding of anti-cancer drugs to hmgb1 is stronger in DNA triplex state as compared to hmgb1 alone, suggesting the combination therapy as a better option. Conclusion: Therefore, the ability of hmgb1 targeted triplex-forming oligonucleotide in combination with triplex selective anticancer drug holds promise in the treatment of malignancies associated with hmgb1 overexpression. The result obtained may open up new vistas to provide a basis for the rational drug design and searching for high-affinity ligands with a high triplex selectivity.

Background: Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine Dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1. Methods: After the IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods, including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured, and changes in the cell cycle were analyzed. Results: AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit the cell cycle in pancreatic cancer cell lines. Conclusion: In conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

Background: The quinoline scaffold has been an attraction due to its pharmacological activities such as anti-HIV, anti-neoplastic, anti-asthmatic, anti-tuberculotic, anti-fungal, and anti-bacterial. Objective: The designed quinoline-3-carboxylate derivatives were synthesized through a two-step reaction and evaluated for antiproliferative activity against MCF-7 and K562 cell lines. Methods: Synthesized compounds were characterized by modern analytical techniques like NMR, 2DNMR, mass, and IR. Moreover, the purity of compounds was analyzed through the HPLC. In the progress of biological results, all synthesized compounds were evaluated for antiproliferative activity against MCF-7 and K562 cell lines. Results: The synthesized compounds exhibited micromolar inhibition in all over the ranges, however, some of the compounds showed better activity than the standard anticancer drug such, as 4m and 4n with the IC50 value of 0.33μM against the MCF-7 cell line, and the compounds 4k and 4m showed potential activity against the K562 cell line with the IC50 value of 0.28μM. The anti-cancer activities of compounds were found to be through the up-regulation of intrinsic apoptosis pathways. Conclusion: The biological data of all compounds in both cell lines were utilized for the structural activity relationship of the quinoline-3-carboxylate pharmacophore. The active lead was further validated through rigorous in silico studies for the drug-likeness (QED) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Here in the present research is utilized for the demonstration of an important pharmacophore, which could be utilized for further development to become a lead as an anticancer agent with minimal toxicity.