Recent Patents on Anti-Cancer Drug Discovery - Volume 17, Issue 4, 2022

Local anesthetics are voltage-gated sodium channel blockers primarily administered locally or to the innervating nerves for anesthetic or analgesic purposes. In vitro studies have found direct effects of local anesthetics on cancer cells, such as impact on cancer cell proliferation, apoptosis, migration, invasion, and chemosensitivity, by multiple mechanisms. So far, in vivo evidence regarding the effect of local anesthetics on cancer cell lines is relatively lacking. Local and regional anesthesia administration has been reported to reduce postoperative pain and opioid use in cancer treatment. Additionally, regional anesthesia may reduce the perioperative stress response. However, the clinical therapeutic application of local anesthetics in cancer remains exploratory. In this review, we will discuss the direct and indirect effects of local anesthetics on cancer cells, and discuss the current evidence related to the use of local anesthetics in the treatment of cancer.

Background: Tea, as the bud from the plant Camellia sinensis, is the most consumed popular beverage just next to water; especially green tea has gained much attention because of its health effects. The anticancer effects of tea components including tea polyphenols, in particular epigallocatechin gallate and tea polysaccharides, are widely investigated in recent years. Objectives: Based on the articles and patents published in the last 10 years, this review focuses on the structural activities and molecular mechanisms of the anticancer effects of tea components (mainly tea polyphenols and tea polysaccharides) to provide references for future anticancer studies of tea. Methods: In the database, a literature search was conducted with “tea polyphenols”, “tea polysaccharides”, “theanine” and “anticancer” as the keywords, and the limited time range was “2010-2021”. After sorting out and analyzing the retrieval results, the structure, activity and molecular mechanism, as well as the research progress on the structural modification, drug delivery system and toxicology of natural agents in tea in recent years, were summarized. Results: We found that the natural anticancer agents in tea mainly include tea polyphenols, tea polysaccharides, theanine, caffeine and other components by summarizing the literature. The anticancer mechanisms can be divided into the induction of cell apoptosis, inhibition of cell proliferation, metastasis and invasion, and inhibition of angiogenesis. In the past 10 years, there was little literature on the structural modification, drug delivery system and toxicological evaluation of natural anticancer agents in tea, and there were reports of novel research on nano preparations. The studies showed that nano preparation technology could effectively improve the bioavailability and targeting treatment of anticancer tea components. In addition, in the past decade, patents on tea and natural anticancer agents in tea were relatively rich, among which pharmaceutic preparation patents were the majority, and tea polyphenols were the main ones. Conclusion: This paper concluded that there are many kinds of natural anticancer agents in tea, and the anticancer mechanism is complex. Further research on the structural modification, drug delivery system and toxicological evaluation of relevant anticancer active components can be carried out. In general, tea components as new anticancer substances have a certain potential for development. In addition, future research can be focused on the comprehensive study of the structure-activity relationship, the in-depth study of the molecular mechanism, the in-depth understanding of the anticancer effects in vivo, and the verification of large-scale production.

Background: Breast cancer is the most frequently diagnosed type of cancer in women, accounting for 2.1 million cases, and stands as the fifth leading cause of death. Several treatment strategies are available, such as surgical resection, radiation, hormonal therapy, and conventional chemotherapy; however, these are associated with severe adverse effects in the patients. Objectives: This review aims to summarize the different studies (in vitro, in vivo, and new patents) concerning the therapeutic potential of plant polyphenolics in the management of breast cancer, published in the period fromJanuary 2016 to January 2021. Moreover, this review will focus on the underlying mechanisms of action and molecular characteristics of these compounds. Methods: The data of this review were collected from different scientific databases, such as Pub- Med, Science Direct, Google Scholarship, SciFinder, and Egyptian Knowledge Bank (EKB). Results: During the period 2016-2021, in the in vitro studies, investigation on 52 compounds of polyphenolic nature with promising anti-breast cancer activity has been conducted, while 14 compounds have been reported via in vivo studies. Besides, about 15 compounds have been registered as patent drugs. Different mechanisms of action and molecular targets have been reported, providing a clarified basis and precise reflection of the anticancer properties of these compounds against breast cancer. Conclusion: Polyphenolics represent a comprehensive source of anticancer lead compounds against the progression of breast cancer invasion and metastasis.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with a poor prognosis. Therefore, it is imperative to develop new prognostic or therapeutic biomarkers for TNBC. Objectives: To explore the prognostic and therapeutic values of autophagy-related genes (ARGs) in TNBC. Methods: Overall, 157 TNBC patients’ data were obtained from The Cancer Genome Atlas database, and the ARGs were acquired from the Human Autophagy Database. Differentially expressed ARGs (DEGs) between tumor and normal tissues were identified, and the prognostic ARGs were developed using R software. Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves were both used to evaluate the accuracy of the signature. Patents about prognostic ARGs were reviewed through Worldwide Espacenet® and Patentscope®. Results: We obtained 28 DEGs and two prognostic ARGs (EIF4EBP1 and PARP1). The Kaplan- Meier survival curves showed that the survival rate of patients with low 2-ARG signature risk score was significantly higher than that of patients with high-risk score (P =0.003). ROC at 5 years indicated that the signature had good prognostic accuracy (AUC =0.929). The signature was independent of T, N, M, and TNM stages (P <0.05). The patent review suggested that many mTOR inhibitors alone or in combination with another anticancer agent have been provided for the treatment of many cancers and shown promising results. No drug patents about PARP1 overexpression were disclosed. Conclusion: We developed a 2-ARG signature (EIF4EBP1 and PARP1), which was an independent prognostic biomarker for TNBC. As EIF4EBP1 was upregulated in TNBC, mTOR inhibitors which blocked the mTOR/4EBP1/eIF4E pathway, may be a promising therapeutic strategy for TNBC.

Background: Therapeutic resistance is a frequent problem of cancer treatment and a leading cause of mortality in patients with metastatic colorectal cancer (CRC). Recent insight into the mechanisms that confer multidrug resistance has elucidated that the ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) assists cancer cells in escaping therapeutic stress caused by toxic chemotherapy. Therefore, it is necessary to develop ABCG2 inhibitors. Objectives: In the present study, we investigated the inhibitory effect of KU55933 on ABCG2 in CRC. Methods: The cytotoxicity assay and drug accumulation assay were used to examine the inhibitory effect of KU55933 on ABCG2. The protein expressions were detected by Western blot assay. The docking assay was performed to predict the binding site and intermolecular interactions between KU55933 and ABCG2. Results: KU55933 was more potent than the known ABCG2 inhibitor fumitremorgin C to enhance the sensitivity of mitoxantrone and doxorubicin and the intracellular accumulation of mitoxantrone, doxorubicin and rhodamine 123 inside CRC cells with ABCG2 overexpression. Moreover, KU55933 did not affect the protein level of ABCG2. Furthermore, the docking data showed that KU55933 was tightly located in the drug-binding pocket of ABCG2. Conclusion: In summary, our data presented that KU55933 could effectively inhibit the drug pump activity of ABCG2 in colorectal cancer, which is further supported by the predicted model that showed the hydrophobic interactions of KU55933 within the drug-binding pocket of ABCG2. KU55933 can potently inhibit the activity of ABCG2 in CRC.

Background: Lung cancer is a malignant tumor with a high incidence in China, especially non-small cell lung cancer (NSCLC), which is the main threat to human life, with terrible morbidity and mortality. The research on the treatment and mechanism of NSCLC has been the forefront and hotspot of research. Recent patents show that alpha-solanine (α-solanine) exhibits the best anti-cancer activity, although its target and related mechanism remain to be elucidated. Objectives: This study aims to explore the possible targets and mechanisms of α-solanine in the treatment of NSCLC through network pharmacology and experimental verification. Methods: Network pharmacology was applied to screen the possible targets of α-solanine on NSCLC, construct core networks, and perform GO enrichment and KEGG pathway analysis to predict the mechanism of α-solanine against NSCLC. Experiments were implemented to verify the results of network pharmacology in vitro. The A549 and PC-9 cells were exposed to α-solanine to assess the anti-tumor effect. Cell apoptosis was determined by the Annexin-V/PI assay. Targeted energy metabolomics was used to validate the network pharmacology results, and energy metabolism pathway- related proteins were detected by immunofluorescence and western blot. Results: Network pharmacology showed that there were 130 potential targets of α-solanine and NSCLC. GO, and KEGG analysis showed that the energy metabolism pathway is the main pathway for α-solanine to exert anti-tumor effects on NSCLC. Experimental results showed that α-solanine inhibited cell proliferation, migration, invasion and promoted cell apoptosis. At the same time, after α-solanine treatment, the energy metabolism pathway-related proteins, including GPI, ALDOA, TPI1, PKLR, LDHA, and ALDH3, were expressed reduced. In addition, α-solanine also affects the amino acid metabolism of A549 and PC-9 cells. Conclusion: Based on a combination of network pharmacological prediction and experimental verification, α-solanine may exert anti-NSCLC effects by regulating the energy metabolism pathway.

Background: In most communities, the risk of developing breast cancer is increasing. By affecting the cyclooxygenase 1 and 2 (COX-1 and COX-2) enzymes and actin filaments, acetylsalicylic acid (Aspirin) has been shown to reduce the risk of breast cancer and prevent cell migration in both laboratory and clinical studies. Methods: The purpose of this study is to determine the mechanical properties of normal and cancerous breast tissue cells, as well as the short-term effect of aspirin on cancer cells. To this end, the mechanical properties and deformation of three cell types were investigated: healthy MCF-10 breast cells, MCF-7 breast cancer cells, and MCF-7 breast cancer cells treated with a 5 μM aspirin solution. Atomic Force Microscopy (AFM) was used to determine the mechanical properties of the cells. Cell deformation was analyzed in all groups, and Young's modulus was calculated using the Hertz model. Results: According to the obtained data, cancer cells deformed at a rate half that of healthy cells. Nonetheless, when aspirin was used, cancer cells deformed similarly to healthy cells. Additionally, healthy cells' Young's modulus was calculated to be approximately three times that of cancer cells, which was placed closer to that of healthy cells by adding aspirin to Young's modulus. Conclusion: Cell strength appears to have increased due to aspirin's intervention on actin filaments and cytoskeletons, and the mechanical properties of breast cancer cells have become more similar to those of normal cells. The likelihood of cell migration and metastasis decreases as cell strength increases.

Background: The incidence of melanoma has been increasing over the last 30 years. The most common treatments, such as surgery, chemotherapy, and radiotherapy, frequently cause serious damage to the body. It is therefore critical to develop a new therapeutic strategy for the treatment of melanoma. Objectives: This research aims to evaluate the anti-tumor effect of Neochamaejasmine A (NCA) on B16F10 melanoma cells and the underlying molecular mechanisms. Methods: The CCK-8 kit was utilized to assay the influence of NCA on the vitality of B16F10 cells. Modifications in B16F10 cells morphology were observed using a phase-contrast microscope. Apoptosis of B16F10 melanoma cells was assessed by Hoechst 33258, Annexin V and propidium iodide staining. Cell cycle was detected using a commercial kit by flow cytometry. The mRNA and protein expression levels associated with apoptosis and cell cycle arrest were detected by RT-PCR and Western blot. The expression level of pathway proteins was assessed using Western blot. Results: It was found that the proliferation of B16F10 cells was inhibited by NCA in concentration- and time-dependent manners. NCA promoted apoptosis by halting the cell cycle at the G2/M phase. After treatment with NCA, cell apoptosis was confirmed by Hoechst 33258 staining. NCA triggered the cell cycle to seize at the G2/M stage by downregulating cyclin B1 and cyclin-dependent kinase 2 (CDC2) expression. Moreover, the mRNA and protein expression of cleaved caspase- 9 and Bcl-2-associated X-protein (Bax) were increased, whereas there was a decline in the expression of B-cell lymphoma 2 (Bcl-2). The p-p38/p38 and phosphorylated c-Jun N-terminal kinase (p-JNK/JNK) ratio were also elevated by NCA. The apoptosis and G2/M cell cycle arrest were inhibited in cells co-treated with the p38 inhibitor SB203580 and JNK inhibitor SP600125. The expression of apoptosis-related proteins Bax was decreased, and Bcl-2 was increased. Conclusion: The findings of this study showed that NCA could induce apoptosis and cell cycle arrest in B16F10 melanoma cells by activating JNK and p38 MAPK signaling pathway.

Background: Angiogenesis is a hallmark of cancer, which is regulated by diverse factors, including long non-coding RNAs (lncRNAS). Our previous study showed that the long non-coding RNA H22954 inhibits tumor growth, albeit whether it is involved in the angiogenesis of cancer re-mains unknown. Objectives: This study aimed to investigate the role of lncRNA H22954 in angiogenesis of acute myeloid leukemia (AML) and the underlying molecular mechanism. Methods: Bioinformatics analysis was conducted to screen the targeted molecule of H22954. Western blot and ELISA analysis detected PDGFA protein expression, and RT-qPCR detected H22954 and PDGFA expression in cell lines and AML samples. Dual-luciferase reporter gene assay and half-life assay were applied to validate the relationship between H22954 and PDGFA. The functional experi-ment was conducted to investigate the role of H22954 in tube formation. Results: Overexpression of H22954 inhibited angiogenesis in mouse xenograft tumors and cultured acute myeloid leukemia (AML) cells. Bioinformatics analysis and luciferase assay revealed that H22954 targeted the 3’ untranslated region (UTR) of the platelet-derived growth factor subunit A (PDGFA) gene. In transfected cells, H22954 overexpression reduced PDGFA expression and protein levels. Tube formation was rescued following the addition of exogenous human PDGFA to the con-ditioned medium from cells overexpressing H22954. The expression of H22954 in K562 cells re-duced the half-life of PDGFA mRNA. Furthermore, H22954 expression was inversely correlated with PDGFA expression in patient samples. Conclusion: These findings indicate that H22954 inhibits angiogenesis in AML through the down-regulation of PDGFA expression. Administering recombinant lncRNA H22954 may be a therapeutic approach for patients with AML.