Recent Patents on Anti-Cancer Drug Discovery - Volume 17, Issue 3, 2022

Background: In recent years, many naphthoquinone compounds with anticancer activity have been identified in Arnebiae Radix, and some of them have the potential to be developed into anticancer drugs. Objective: This article aimed to provide a comprehensive overview of the anticancer effects of naphthoquinone compounds through a detailed review of literature and Chinese patents, and discuss their potential to be developed as anticancer drugs for clinical application. Methods: Research papers were collected through the databases of PubMed, Cnki and SciDirect using keyword searches “naphthoquinone compounds” and “anticancer”. The keywords of “shikonin” and “shikonin derivatives” were also used in PubMed, Cnki and SciDirect databases to collect research articles. The Chinese patents were collected using the Cnki patent database. Results: Naphthoquinone compounds have been found to possess anti-cancer activity, and their modes of action are associated with inducing apoptosis, inhibiting cancer cell proliferation, promoting autophagy in cancer cells, anti-cancer angiogenesis and inhibition of cell adhesion, invasion and metastasis, inhibiting glycolysis and inhibiting DNA topoisomerase activity. Conclusion: Most of the naphthoquinone compounds show effective anti-cancer activity in vitro. The structure modification of naphthoquinone aims to develop anti-cancer drugs with high efficacy and low toxicity.

Background: (su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9 (SET7/9) is a member of the protein lysine methyltransferases (PLMTs or PKMTs) family. It contains a SET domain. Recent studies demonstrate that SET7/9 methylates both lysine 4 of histone 3 (H3-K4) and lysine(s) of non-histone proteins, including transcription factors, tumor suppressors, and membrane-associated receptors. Objective: This article mainly reviews the non-histone methylation effects of SET7/9 and its functions in tumorigenesis and development. Methods: PubMed was screened for this information. Results: SET7/9 plays a key regulatory role in various biological processes such as cell proliferation, transcription regulation, cell cycle, protein stability, cardiac morphogenesis, and development. In addition, SET7/9 is involved in the pathogenesis of hair loss, breast cancer progression, human carotid plaque atherosclerosis, chronic kidney disease, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Conclusion: SET7/9 is an important methyltransferase, which can catalyze the methylation of a variety of proteins. Its substrates are closely related to the occurrence and development of tumors.

The Notch signaling pathway is an evolutionarily conserved pathway usually present in multicellular organisms, which plays a pivotal role in cell fate determination and proliferation. Due to this property, it is known to be highly oncogenic, especially in the dysregulated version of the Notch pathway, where apoptosis is inhibited and abnormal cell growth is supported. Notch receptors and ligand proteins play an essential role in cancers, such as myeloid leukemia, T-cell lymphoblastic leukemia, and organ-specific, i.e., breast, colon, pancreas, and skin cancers. Any type of cancer generates due to genetic defects, including epigenetic alterations and mutations. The researchers can use these alterations to find a promising diagnostic as well as therapeutic tool for cancer. The successful inhibition of the Notch pathway with the help of specific biomarkers or suppression of gene expression represents a new remedy in cancer research. This article focuses on the various remedies hidden within the Notch pathway's mechanism, primarily based on different patents published in recent years for assisting cancer diagnosis and succeeding treatment.

Background: Transdermal drug delivery is an emerging and appealing alternative to oral and hypodermic drug delivery systems. With the new developments in skin penetration techniques, anticancer drugs ranging from hydrophilic macromolecules to lipophilic drugs can be administered via a transdermal route to treat cancer. Objective: In the present review, various approaches to enhance the transdermal delivery of drugs are discussed, including micro and nanotechnology-based transdermal formulations like chemotherapy, gene therapy, immunotherapy, phototherapy, vaccines, and medical devices. Limitations and advantages of various transdermal technologies are also elaborated. Methods: In this review, patent applications and recent literature of transdermal drug delivery systems employed to cure mainly cancer are covered. Results: Transdermal drug delivery systems have proved their potential to cure cancer. They increase the bioavailability of the drug by site-specific drug delivery and can reduce the side effects/- toxicity associated with anticancer drugs. Conclusion: The potential of transdermal drug delivery systems to carry the drug may unclutter novel ways for therapeutic intercessions in various tumors.

Background: The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. Objective: This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. Methods: We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. Results/Conclusion: Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition- associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-ΚB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors’ anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.

Background: Finding novel antitumor reagents from naturally occurring alkaloids is a widely accepted strategy. Evodiamine, a tryptamine indole alkaloid isolated from Evodia rutaecarpa, has a wide range of biological activities, such as anti-tumor, anti-inflammation, and anti-bacteria. Hence, research on the structural modification of evodiamine will facilitate the discovery of new antitumor drugs. Objective: The recent advances in the synthesis of evodiamine, and studies on the drug design, biological activities, and structure-activity-relationships of its derivatives, published in patents and primary literature, are reviewed in this paper. Methods: The literature, including patents and follow-up research papers from 2015 to 2020, related to evodiamine is searched in the Scifinder, PubMed, Espacenet, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The keywords are evodiamine, synthesis, modification, anticancer, mechanism. Results: The synthesis of evodiamine is summarized. Then, structural modifications of evodiamine are described, and the possible modes of action are discussed. Conclusion: Evodiamine has a 6/5/6/6/6 ring system, and the structural modifications are focused on rings A, D, E, C5, N-13, and N-14. Some compounds show promising anticancer potentials and warrant further study.

Background: Shikonin (SKN), a naturally occurring naphthoquinone, is a major active chemical component isolated from Lithospermum erythrorhizon Sieb Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge, and commonly used to treat viral infection, inflammation, and cancer. However, its underlying mechanism has not been elucidated. Objective: This study aims to explore the antitumor mechanism of SKN in colorectal cancer (CRC) through network pharmacology and cell experiments. Methods: SymMap database and Genecards were used to predict the potential targets of SKN and CRC, while the cotargets were obtained by Venn diagram. The cotargets were imported into the website of String and DAVID, constructing the protein-protein interaction (PPI) network, performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, the Compound-Target-Pathway (C-T-P) network was generated by connecting potential pathways with the corresponding targets. Results: According to the results of network pharmacological analysis, the cell experiments were used to verify the key signal pathway. The most relevant target of SKN for the treatment of CRC was PI3K/Akt signaling pathway. SKN inhibited CRC cells (HT29 and HCT116) proliferation, migration, and invasion, and promoted cell apoptosis by targeting IL6 and inhibiting the IL6R/PI3K/Akt signaling pathway. SKN promotes apoptosis and suppresses CRC cells’ (HT29 and HCT116) activity through the PI3K-Akt signaling pathway. Conclusion: This research not only provided a theoretical and experimental basis for more in- -depth studies but also offered an efficient method for the rational utilization of a series of Traditional Chinese medicines as anti-CRC drugs.

Background: Cervical cancer is the fourth most prevalent gynecological cancer worldwide, which threatens women's health and causes cancer-related mortality. In the search for effective anticervical cancer drugs, we discovered that β-estradiol (E2), a potent drug for estrogen deficiency syndrome treatment, displays the most potent cytotoxicity against HeLa cells. Objective: This study aims to evaluate the growth inhibitory effect of β-estradiol on HeLa cells and explore its underlying mechanisms. Methods: CCK-8 assay was used to evaluate the cytotoxicity of 6 compounds against HeLa cells. Flow cytometric analysis and Hoechst 33258 staining assay were performed to detect cell cycle arrest and apoptosis induction. The collapse of the mitochondrial potential was observed by the JC-1 staining assay. The expression levels of proteins were examined by western blotting. Results: β-Estradiol, at high concentration, displays potent cytotoxicity against HeLa cells with an IC50 value of 18.71 ± 1.57 μM for 72 h treatment. β-Estradiol induces G2/M cell cycle arrest through downregulating Cyclin B1 and p-CDK1. In addition, β-estradiol-induced apoptosis is accompanied by the loss of mitochondrial potential, activation of the Caspase family, and altered Bax/Bcl-2 ratio. β-Estradiol markedly decreased the expression level of p-AKT and p-NF-ΚB. Conclusion: This study demonstrated that β-estradiol induces mitochondrial apoptosis in cervical cancer through the suppression of AKT/NF-ΚB signaling pathway, indicating that β-estradiol may serve as a potential agent for cervical cancer treatment.