Recent Patents on Anti-Cancer Drug Discovery - Volume 17, Issue 2, 2022

Background: Fruits are an important dietary component, which supply vitamins, minerals, as well as dietary fiber. In addition, they are rich sources of various biological and pharmacologically active compounds. Among these, temperate fruits are well studied for their pharmacological potentials, whereas tropical/subtropical fruits are less explored for their health impacts. In India, most of the consumed fruits are either tropical or subtropical. Objectives: This mini review aims to provide a health impact of major tropical and sub-tropical fruits of India, emphasizing their anticancer efficacy. In addition, the identified bioactive components from these fruits exhibiting anticancer efficacy are also discussed along with the patent literature published. Methods: The literature was collected from various repositories, including NCBI, ScienceDirect, Eurekaselect, and Web of Science; literature from predatory journals was omitted during the process. Patent literature was collected from google patents and similar patent databases. Results: Tropical fruits are rich sources of various nutrients and bioactive components including polyphenols, flavonoids, anthocyanin, etc. By virtue of these biomolecules, tropical fruits have been shown to interfere with various steps in carcinogenesis, metastasis, and drug resistance. Their mode of action is either by activation of apoptosis, regulation of cell cycle, inhibition of cell survival and proliferation pathways, increased lipid trafficking or inhibiting inflammatory pathways. Several molecules and combinations have been patented for their anticancer and chemoprotective properties. Conclusion: Overall, the present concludes that Indian tropical/ subtropical fruits are nutritionally and pharmacologically active and may serve as a source of novel anticancer agents in the future.

Intestinal microecology is the largest and most complex human microecology. The intestinal microflora plays an important role in human health. Imbalance of intestinal microflora contributes to the occurrence and development of many diseases. Recently, the treatment of human diseases by regulating intestinal microflora has become a research topic of interest. Traditional Chinese medicine considers the whole human body as the central concept in disease treatment strategies. It advocates maintaining the coordination and balance of the functions of various organs and systems of the human body, including the intestinal microflora. Traditional Chinese medicine improves the metabolism and immune function of the human body by regulating the intestinal microflora. The intestinal microflora could trigger pharmacological activity or reduce toxicity of drugs through regulating metabolism, which enables traditional Chinese medicine formulations to exert their best therapeutic effects. This review summarized the relationship between the intestinal microflora and digestive system, tumors, and other diseases. Furthermore, the role of traditional Chinese medicine in the treatment of tumors, and other diseases is discussed. The relationship among traditional Chinese medicine and the common intestinal microflora, pathogenesis of human diseases, and effective intervention methods were elaborated. In addition, we explored the research progress of traditional Chinese medicine in the treatment of various human diseases by regulating intestinal microflora to provide new treatment concepts. There is a close relationship between traditional Chinese medicine and the intestinal microflora. Traditional Chinese medicine formulations contribute to maintain the natural balance of the intestinal tract and the intestinal microflora to achieve treatment effects. This paper summarizes the mechanism of action of traditional Chinese medicine formulations in regulating the intestinal microflora in the prevention and treatment of various diseases. Furthermore, it summarizes information on the application of the interaction between traditional Chinese medicine preparations and the regulation of intestinal microflora in the treatment of common human diseases. Intestinal microflora plays a key role in traditional Chinese medicine in maintaining the natural balance of physiology and metabolism of human body. It will provide a theoretical basis for the traditional Chinese medicine preparations in the prevention and treatment of common human diseases, and simulate future research on this aspect.

Background: Plants that are rich in triterpenoid compounds possess various biological activities and are reported in many scientific works. Triterpenoids, because of their broad sources, wide variety, high medicinal value, and anti-tumor properties, have drawn great attention from scientists. However, the lack of approach to understand the link between their chemical structures and biological activities has limited the fundamental comprehension of these compounds in cancer therapy. Objective: The aim of the study is to summarize the list of plants with triterpenoids and their derivatives that are a source of potential novel therapeutic anti-cancer agents by interpreting the network of anti-cancer activity and the structures of triterpenoids and their derivatives. Methods: This work focuses on analyzing relevant patents and references that detail the structure of triterpenoids and their derivatives for the treatment of tumors. Results: Pentacyclic triterpenoid plays a more important role in improving the autophagic signaling pathways of cancer cells compared to tetracyclic triterpenoid. Conclusion: The heterogenous skeleton structure of triterpenoids impairs programmed cell death signaling pathways in various cancers.

Background: Astroglioma is the most common primary tumor of the central nervous system. Currently, there is no effective treatment for astroglioma. In the present study, the extract (L3) from Ganoderma Lucidum (G. lucidum) was found to inhibit the growth of astroglioma U87 cells and change the expression of circular RNAs (circRNAs). One of these, including the circular NF1-419 (circNF1-419), was of interest because NF1 gene is a classic tumor suppressor gene. Objectives: The functional role of circ-NF1-419 in the inhibition of astroglioma cells remains unknown. This study focuses on the role of circNF1-419 in functional abnormalities of U87 astroglioma cells and aims to elaborate on its regulatory mechanism. Methods: The circNF1-419 overexpressing U87 (U87-NF1-419) cells were constructed. We generated U87-NF1-419 to evaluate the role of circNF1-419 on cell cycle, apoptosis, proliferation, tumor growth and metabolic regulation. Finally, we used docking screening to identify compounds in G. lucidum extracts that target circ-419. Results: U87-NF1-419 can promote cell apoptosis and regulate lipid metabolism through glycerophospholipid metabolism and retrograde endocannabinoid signaling. Further examinations revealed that the expression of metabolic regulators, such as L-type voltage-operated calcium channels (L-VOCC), phospholipase C-β3 (PLCβ3), Mucin1, cationic amino acid transporter 4 (CAT4), cationic amino acid transporter 1 (CAT1) and a kinase (PRKA) anchor protein 4 (AKAP4) was inhibited, while phosphatidylserine synthase 1 (PTDSS1) was enhanced in U87-NF1-419 cells. In vivo experiments showed that circNF1-419 inhibits tumor growth in BALB/C nude mice, and enhanced AKAP4 and PTDSS1 in tumor tissues. The virtual docking screening results supported that ganosporeric acid A, ganodermatriol, ganoderic acid B and α-D-Arabinofuranosyladenine in L3 could activate circNF1-419 in astroglioma treatment. Conclusion: This study indicated that circNF1-419 could be a therapeutic target for the clinical treatment of astroglioma. L3 from Ganoderma Lucidum (G. lucidum) could inhibit astroglioma growth by activating circNF1-419.

Background: Vincristine (VCR) is a chemotherapeutic drug commonly used in the treatment of Colorectal Cancer (CRC). However, VCR drug resistance may result in reduced efficacy and even failure of chemotherapy in CRC treatment. MiRNA has been demonstrated to be associated with the sensitivity of tumor cells to chemotherapy. Objectives: This study aimed to identify a novel miRNA-14669 that can reverse vincristine resistance and sensitize drug-resistant colorectal cancer cells. Methods: High-throughput sequencing was performed to screen miRNAs that are associated with VCR drug resistance, and qRT-PCR was used for further validation. The miRNA mimic and inhibitor were designed and transfected into HCT-8,HCT-116 and HCT-8/VCR cells. Wound healing test examined the effect of the miRNA on the migration of colorectal cancer cells. Flow cytometry was used to evaluate cell apoptosis of HCT-8 cells. Survivin, Bcl-2, GST3, MDR1 and MRP1 expressions were detected by Western blot. Results: The expression of miRNA-14669 in HCT-8/VCR cells was 1.925 times higher than that of the HCT-8 cells. After transfecting with mimic miRNA, HCT-8 and HCT-116 cells showed an increased survival rate. The survival rate of HCT-8/VCR cells decreased by transfection of inhibitor. The inhibitor also sensitized HCT-8 and HCT-116 cells to VCR or 5-Fluorouracil (5-FU). The migratory ability of HCT-8 and HCT-116 cells increased by miRNA mimic while reduced by miRNA inhibitor. Overexpression of miRNA-14669 reduced apoptosis, while downregulation of miRNA- 14669 increased cell apoptosis in HCT-8 cells. The mechanism of the miRNA involved in drug resistance may be attributed to apoptosis of tumor cells, detoxification of GST3 and drug efflux induced by MDR1 and MRP1. PI3K / AKT is the signaling pathway related to drug resistance. Conclusion: We identified a novel miRNA-14669 that may be associated with the chemotherapeutic resistance in CRC cells.

Background: Colon cancer is one of the most common types of cancer worldwide. Multiple studies have unveiled the key role of microRNAs (miRNAs) in the development of various types of cancer. However, the mechanism of action of miR-125b in the development and progression of colon cancer remains unknown. Objectives: In this study, we explored the association of miR-125b and signal transducer and activator of transcription 3 (STAT3) and its role in the proliferation and apoptosis of SW480 colon cancer cells. Methods: The miR-125b expression in NCM460, SW480, HT29, and HCT8 cells was detected using quantitative real-time polymerase chain reaction (qRT-PCR). SW480 cells were transfected with lentiviruses of GFP-miR-125b and GFP-NC to establish a stable miR-125b overexpression colon cancer cell model and a control model. The targeting relationship between miR-125b and STAT3 was analyzed using bioinformatics and verified by the dual-luciferase reporter gene assay. Cell proliferation and apoptosis were assessed using the Cell Counting Kit-8 assay and TUNEL staining. The expression levels of STAT3, Bcl-2, and Bax were analyzed using Western blot analysis. Results: It was found that the relative mRNA expression of miR-125b was decreased in SW480, HT29, and HCT8 cells compared with that in NCM460 cells (P<0.05). The luciferase reporter gene assay confirmed that miR-125b downregulated the STAT3 gene expression (P<0.05). Overexpression of miR-125b inhibited proliferation and promoted apoptosis in SW480 colon cancer cells and was accompanied by upregulated Bax expression and downregulated Bcl-2 expression (P<0.05). Re-expression of STAT3 promoted cell proliferation and inhibited cell apoptosis, whereas Bcl-2 expression increased, and Bax expression decreased (P<0.05). Conclusion: The miR-125b regulates the expression of Bax and Bcl-2 by downregulating the expression of STAT3, thereby inhibiting proliferation and inducing apoptosis of SW480 colon cancer cells.

Background: Cyclophosphamide is approved for the treatment of a variety of tumors, yet the use of cyclophosphamide is limited by kidney and liver toxicity. In the clinic, the Wuzhi capsule is approved to attenuate cyclophosphamide toxicity in the kidney and liver. Objectives: We aimed to investigate the effects of the principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclophosphamide. Methods: The essential pharmacokinetic data and physicochemical parameters of SIA, STA, and cyclophosphamide were collected. Physiologically based pharmacokinetic (PBPK) models of SIA, STA, and cyclophosphamide were built in Simcyp Simulator and verified using published clinical pharmacokinetic data. The verified PBPK models were used to predict potential herb-drug interactions (HDIs) between cyclophosphamide and SIA and STA in cancer patients. Results: The area under the plasma concentration–time curve (AUC) of cyclophosphamide was increased by 18% and 1% when co-administered with STA and SIA at a single dose, respectively, and increased by 301% and 29% when co-administered with STA and SIA at multiple doses, respectively. The maximum concentration (Cmax) of cyclophosphamide was increased by 75% and 7% when co-administered with STA and SIA at multiple doses, respectively. Conclusion: The AUC and Cmax of cyclophosphamide were increased when cyclophosphamide was combined with the Wuzhi capsule, compared to cyclophosphamide alone. Our study shows that the adverse drug reactions and toxicity of cyclophosphamide should be closely monitored and an effective dosage adjustment of cyclophosphamide may need to be considered when co-administered with the Wuzhi capsule.

Background: The use of health-related applications (apps) on smartphones has become widespread. This is especially of value during the ongoing SAR-COV-2 pandemic, where accessibility to health care services has been greatly limited. Patients with free access to apps can obtain information to improve their understanding and management of health issues. Currently, there are cancer-related apps available on iPhones and androids. However, there are no guidelines to control these apps and ensure their quality. Furthermore, these apps may significantly modify the patients’ perception and knowledge about drug-related health services. Objectives: The aim of this study was to assess the convenience, quality, safety and efficacy of apps for cancer patient care. Methods: The study was conducted by searching all apps related to cancer care on both Google Play Store and Apple iTunes Store. A detailed assessment was then performed using the mobile application rating scale (MARS) and risk assessment tools. Results: The results indicated that on a scale from 1-5, 47% of the apps were rated ≥ 4. The MARS assessment of the apps yielded an overall quality rating of 3.38 ± 0.9 (mean ± SD). The visual appeal of the app was found to have a significant effect on app functionality and user engagement. The potential benefits of these apps come with challenges and limitations. Patents related to smartphone applications targeting patients were also discussed. Conclusion: We recommend a greater emphasis toward producing evidence-based apps. These apps should be rigorously tested, evaluated and updated by experts, particularly clinical pharmacists. Also, these apps may alter patient attitudes toward services provided by physicians and pharmacists. Finally, these apps should not replace in-person interactive health services.