Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 8, 2022

Gastric cancer is a global cancer with a high mortality rate. A growing number of studies have found the abnormal expression of lncRNA (long noncoding RNA) in many tumors, which plays a role in promoting or inhibiting cancer. Similarly, lncRNA abnormal expression plays an essential biological function in gastric cancer. This article focuses on lncRNA involvement in the development of gastric cancer in terms of cell cycle disorder, apoptosis inhibition, metabolic remodeling, promotion of tumor inflammation, immune escape, induction of angiogenesis, and Epithelial Mesenchymal Transition (EMT). The involvement of lncRNA in the development of gastric cancer is related to drug resistance, such as cisplatin and multi-drug resistance. It can also be used as a potential marker for the diagnosis and prognosis of gastric cancer and a target for the treatment. With an in-depth understanding of the mechanism of lncRNA in gastric cancer, new ideas for personalized treatment of gastric cancer are expected.

Background: Cancer can be considered as a genetic as well as a metabolic disorder. The current cancer treatment scenario looks like aggravating tumor cell metabolism, causing the disease to progress even with greater intensity. The cancer therapy is restricted to the limitations of poor patient compliance due to toxicities to normal tissues and multi-drug resistance development. There is an emerging need for cancer therapy to be more focused towards better understanding of genetic, epigenetic and transcriptional changes resulting in cancer progression and their relationship with treatment sensitivity. Objective: The 4-thiazolidinone nucleus possesses marked anticancer potential towards different biotargets, thus targeting different cancer types like breast, prostate, lung, colorectal and colon cancers, renal cell adenocarcinomas and gliomas. Therefore, conjugating the 4-thiazolidinone scaffold with other promising moieties or directing the therapy towards targeted drug delivery systems like the use of nanocarrier systems, can provide the gateway for optimizing the anticancer efficiency and minimizing the adverse effects and drug resistance development, thus providing stimulus for personalized pharmacotherapy. Methods: An exhaustive literature survey has been done to give an insight into the anticancer potential of the 4- thiazolidinone nucleus either alone or in conjugation with other active moieties, with the mechanisms involved in preventing proliferation and metastasis of cancer covering a vast range of publications of repute. Conclusion: This review aims to summarise the work reported on anticancer activity of 4-thiazolidinone derivatives covering various cancer biomarkers and pathways involved, citing the data from the year 2005 till now, which may be beneficial to the researchers for future development of more efficient 4-thiazolidinone derivatives.

Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer cases increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to halt of DNA replication and eventual cell death. Nitrogen lone pairs of ‘nitrogen mustard’ produce an intermediate 'aziridinium ion' at the molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the Structure Activity Relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability.

One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to tumor-targeting vectors selectively deliver high amount of radiation to cancer cells.²²⁵Ac, ²¹²Bi, ²¹¹At, ²¹³Bi, and 223Ra have been investigated by plenty of clinical trials and preclinical researches for the treatment of smaller tumor burdens, micro-metastatic disease, and post-surgery residual disease. In order to send maximum radiation to tumor cells while minimizing toxicity in normal cells, a high affinity of targeting vectors to cancer tissue is essential. Besides that, the stable and specific complex between chelating agent and α-emitters was found as a crucial parameter. The present review was planned to highlight recent achievements about TAT-based targeting vectors and chelating agents and provide further insight for future researches.

Cancer is the leading cause of mortality and morbidity worldwide. The side effects of cancer treatment affect the quality of life. Cancer patients search for antioxidant dietary supplements and natural products during or after conventional cancer treatment for the alleviation of side effects, improvement of the benefits of treatment, and promotion of well-being. However, the efficacy and safety of these products remain controversial; moreover, previous data do not support the standardized use of those alternative treatments in clinics. The current study reviewed the manuscripts reporting the administration of antioxidants and natural products during cancer treatment and revised preclinical and clinical studies on various types of cancer. Most of the positive results were obtained from experimental animal models; however, human clinical studies are discouraging in this regard. Therefore, further precise and distinguishable studies are required regarding antioxidant dietary supplementation. Future studies are also needed to clarify dietary supplements’ mechanism of action and pharmacokinetics in a suitable cancer patient population that will benefit the therapeutic regimens. Despite the popularity of dietary supplements, clinicians and patients should always consider their potential benefits and risks. Patients should discuss with their physician before taking any dietary antioxidant supplements or natural products.

Background: Cepharanthine (CEP) is an alkaloid extracted from Stephania cepharantha Hayata. This compound has been reported as a promising anti-tumor drug, although its potential molecular mechanism is not fully understood. Here, we studied the anti-tumor effect of CEP on human lung cancer cells and evaluated its molecular mechanism. Methods: The A549 cells were treated with CEP, the cell viability was measured by 3-(4, 5-dimethylthiazolyl-2)-2, 5- diphenyltetrazolium bromide (MTT) assay, and formation of autophagosome was observed by acridine orange staining under a fluorescence microscope. The cell migration and invasion were determined by wound healing and transwell assay. The protein levels of autophagy-associated molecules, light chain 3 (LC3)p38and phospho-p38 in A549 cells, were determined by western blot analysis. Result: The results showed that CEP inhibited cell proliferation, migration and invasion in A549 cells. Moreover, we found that CEP resulted in significant increases in levels of the autophagy marker protein LC3 in A549 cells. The number of intracellular acid dye follicular bright red fluorescence in A549 cells was significantly increased after CEP treatment. At the molecular levels, CEP markedly increased the phosphorylation of p38 in A549 cells. The knockdown of p38 expression by siRNA-p38 impaired the autophagy-regulating effect of CEP. Our results indicated that CEPregulated autophagy was an anti-tumor effect and not a protective response to CEP. Conclusion: Taken together, these results demonstrated that CEP regulated autophagy by activating the p38 signaling pathway, which could be provided a potential application for preventing lung cancer.

Background: Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive malignant non- Hodgkin's lymphoma (NHL) with a poor prognosis. Therefore, novel therapeutic biomarkers and agents must be identified for the same. KAT5 inhibitor, NU 9056, is a small molecule that can inhibit cellular proliferation; however, its role in ENKTL has not been studied. Objective: The present study investigated the effect of NU 9056 in ENKTL cells and explored the possible molecular mechanism for its antitumour effect. Methods: The role of NU 9056 in ENKTL cells was investigated through the Cell Counting Kit-8 assay, flow cytometry, Western blot, and real-time quantitative polymerase chain reaction assay. Results: NU 9056 inhibited ENKTL cell proliferation and induced G2/M phase arrest. NU 9056 also induced apoptosis by upregulating DR4, DR5, and caspase 8 expressions. Additionally, NU 9056 increased the expression of Bax, Bid, and cytochrome C and decreased the expression of Bcl-2, Mcl-1, and XIAP. Furthermore, NU 9056 activated endoplasmic reticulum (ER) stress and inhibited the JAK2/STAT3 signalling pathway. The p38 mitogen-activated protein kinase (MAPK) signalling pathway was also activated by NU 9056, and the ERK signalling pathway was suppressed in natural killer/T cell lymphoma cells. Conclusion: NU 9056 inhibited cell proliferation, arrested cell cycle in the G2/M phase, and induced apoptosis through the stimulation of ER stress, thus inhibiting the JAK2/STAT3 signalling pathway and regulating MAPK pathways in ENKTL cells.

Background: Smoking participates in pathogenesis of lung cancer. Long non-coding RNAs (lncRNAs) play some specific roles during development of lung cancers.

Objective: To investigate effects of smoking on lncRNA alterations in lung cancer.

Methods: There are 522 lung adenocarcinoma (LUAD) and 504 lung squamous cell carcinoma (LUSC) participants. Clinical and lncRNA genetic data were downloaded from The Cancer Genome Atlas (TCGA) database. LncRNA alterations were analyzed in lung cancer patients. Smoking category and packs were evaluated. Correlations between smoking and LncRNA alterations were analyzed. Kaplan-Meier analysis was performed to determine overall survival and disease free survival.

Results: There are more non-smokers in LUSC than in LUAD. In both LUAD and LUSC, smoking could increase total mutation counts and fraction of copy number alterations. Smoking index positively correlated with total mutations in LUAD, but not in LUSC. Smoking could trigger lncRNA alterations both in LUAD and LUSC. Smoking regulated different lncRNA between male and female. EXOC3-AS1 and LINC00603 alterations were positively correlated with smoking index in male LUAD smokers. In female LUAD smokers, smoking index was positively correlated with SNHG15, TP53TG1 and LINC01600 and negatively with LINC00609 and PTCSC3. In both male and female LUSC patients, smoking increased or decreased several lncRNA alterations. DGCR5 alteration increased in male LUSC than in female LUSC patients. In female LUSC patients, LOH12CR2 alteration was positively correlated with smoking index.

Conclusion: Smoking promoted LUAD and LUSC development by affecting different lncRNA alterations in different genders.

Background: Wogonin has been reported to exhibit pharmacological effects against cancer by regulating cell proliferation, metastasis and apoptosis, however, the role of wogonin in hepatocellular carcinoma (HCC) remains poorly elucidated.

Objective: The current study aimed to illustrate whether wogonin influences HCC cell cycle progression and apoptosis by regulating Hippo signaling.

Methods: The effects of wogonin on HCC cell viability, cell cycle progression and apoptosis were analyzed by utilizing CCK-8 and flow cytometry. RNA-seq was employed to analyze the expression profiles between wogonin-treated and control HCC cells, and the selected RNA-seq transcripts were validated by Reverse Transcription-quantitative realtime Polymerase Chain Reaction (RT-qPCR). Immunofluorescence staining was performed to detect the distribution of YAP/TAZ in the nucleus and cytoplasm in HCC cells. Western blotting and human apoptosis array were performed to examine the expression of the indicated genes.

Results: We demonstrated that wogonin induced cell cycle arrest and apoptosis of HCC cell lines SMMC7721 and HCCLM3. RNA-seq analysis showed enrichment in genes associated with cell cycle progression and apoptosis following incubation with wogonin in HCC cells, and the pathways analysis further identified that Hippo signaling pathways highly altered in wogonin-treated cells. Specifically, wogonin increased the phosphorylation of MOB1 and LATS1, promoted translocation of endogenous YAP and TAZ from the nucleus to the cytoplasm, and facilitated phosphorylation of YAP and TAZ. Notably, overexpression of YAP or TAZ partially abrogated the wogonin-mediated HCC cell cycle arrest and apoptosis, and reversed wogonin-mediated suppression of Claspin.

Conclusion: Wogonin induced HCC cell cycle arrest and apoptosis probably by activating MOB1-LATS1 signaling to inhibit the activation of YAP and TAZ, and then decrease the expression of Claspin, suggesting that the understanding of the molecular mechanisms underlying wogonin-induced cell cycle arrest and apoptosis may be useful in HCC therapeutics.

Background: Fomitopsis officinalis (Vill. ex Fr. Bond. et Sing) is a medicinal mushroom, commonly called ‘Agarikon’; it has traditionally been used to treat cough and asthma in the Mongolian population. Objective: The objective of the study was to examine the significance of biological activity of F. officinalis and evaluation of the antioxidant activity and anticancer activity of six fractions of F. officinalis residues (Fo1-powder form dissolved in ethanol, Fo2-petroleum ether residue, Fo3-chloroformic, Fo4-ethylacetate, Fo5-buthanolic, and Fo6-waterethanolic) against hepatocellular carcinoma cells. Methods: We performed in vitro studies of cell proliferation and viability assay, annexin V-FITC/Propidium Iodide assay, and NF-kB signaling pathway by immunoblot analysis. Results: Our findings revealed that all six fractions/extracts have antioxidant activity, and somehow, they exert anticancerous effects against cancer cells. In cancerous cell lines (HepG2 and LO2), Fo3 chloroformic extract promoted the cancer cell apoptosis and cell viability, activated G2/M-phase cell cycle, and selectively induced NF-kB proteins, revealing as a novel antitumor extract. Conclusion: This study reports that Fo3-chloroformic extract is rich in antitumor activity, which was previously not investigated in cancer. To develop the impact of F. officinalis among natural products to treat/prevent oxidative stress disorders or cancers, further examinations of F. officinalis are needed to develop new natural drugs to treat cancer. However, this study assessed only one extract, Fo3-chloroformic, which has a significant impact against cancer cell lines.

Background: Angiogenesis occurs during various physiological or pathological processes such as wound healing and tumor growth. Differentiation of vascular endothelial cells into tip cells and stalk cells initiates the formation of new blood vessels. Tip cells and stalk cells are endothelial cells with different biological characteristics and functions. Objective: The aim of this study was to determine the mechanisms of angiogenesis by exploring differences in gene expression of tip cells and stalk cells. Methods: Raw data were retrieved from NCBI Gene Expression Omnibus (GSE19284). Data were reanalyzed using bioinformatics methods that employ robust statistical methods, including identification of differentially expressed genes (DEGs) between the stalk and tip cells, Weighted Gene Correlation Network Analysis (WGCNA), gene ontology and pathway enrichment analysis using DAVID tools, integration of Protein-Protein Interaction (PPI) networks and screening of hub genes. DEGs of stalk and tip cells were grouped as dataset A. Gene modules associated with differentiation of stalk and tip cells screened by WGCNA were named dataset B. Further, we retrieved existing markers of angiogenesis from previous experimental studies on tip and stalk cells which we called dataset C. Intersection of datasets A, B and C was used as a candidate gene. Subsequently, we verified the results applying Quantitative Polymerase Chain Reaction (Q-PCR) to our clinical specimen. In general, the Q128;PCR results coincide with the majority of the expression profile. Results: We identified five candidate genes, including ESM1, CXCR4, JAG1, FLT1 and PTK2, and two pathways, including Rap1 signaling pathway and PI3K-Akt signaling pathway in vascular endothelial cells that differentiate into tip cells and stalk cells using bioinformatics analysis. Conclusion: Bioinformatics approaches provide new avenues for basic research in different fields such as angiogenesis. The findings of this study provide new perspectives and a basis for the study of molecular mechanisms of vascular endothelial cell differentiation into stalk and tip cells. Genes and pathways identified in this study are potential biomarkers and therapeutic targets for angiogenesis in the tumor.

Background: High relapse and metastasis progression in breast cancer patients have prompted the need to explore alternative treatments. Epigenetic therapy has emerged as an attractive therapeutic strategy due to the reversibility of epigenome structures. Objective: This study investigated the anti-cancer effects of epigenetic drugs scriptaid and zebularine in human breast adenocarcinoma MDA-MB-231 and MCF-7 cells. Methods: First, the half maximal Inhibitory Concentration (IC50) of scriptaid and zebularine, and the combination of both drugs on human breast adenocarcinoma MDA-MB-231 cells were determined. Next, MDA-MB-231 and MCF-7 cells were treated with IC50 of scriptaid, zebularine and the combination of both. After IC50 treatments, the anti-cancer effects were evaluated via cell migration assay, cell cycle analysis and apoptotic studies which included histochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) of the apoptotic genes. Results: Both epigenetic drugs inhibited cell viability in a dose-dependent manner with IC50 of 2 nM scriptaid, 8 μM zebularine and a combination of 2 nM scriptaid and 2 μM zebularine. Both MDA-MB-231 and MCF-7 cells exhibited a reduction in cell migration after the treatments. In particular, MDA-MB-231 cells exhibited a significant reduction in cell migration (p < 0.05) after the treatments of zebularine and the combination of scriptaid and zebularine. Besides, cell cycle analysis demonstrated that scriptaid and the combination of both drugs could induce cell cycle arrest at the G0/G1 phase in both MDA-MB-231 and MCF-7 cells. Furthermore, histochemical staining allowed the observation of apoptotic features, such as nuclear chromatin condensation, cell shrinkage, membrane blebbing, nuclear chromatin fragmentation and cytoplasmic extension, in both MDA-MB-231 and MCF-7 cells after the treatments. Further, apoptotic studies revealed the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 and elevation of Bax/Bcl-2 ratio in MDA-MB-231 cells treated with zebularine and MCF-7 cells treated with all drug regimens. Conclusion: Collectively, these findings suggest that scriptaid and zebularine are potential anti-cancer drugs, either single or in combination, for the therapy of breast cancer. Further investigations of the gene regulatory pathways directed by scriptaid and zebularine are definitely warranted in the future.

Background: Conventional therapies for breast cancer are still a challenge due to cytotoxic drugs not being highly effective with significant adverse effects. Thiohydantoins are biologically active heterocyclic compounds reported for several biological activities, including anticarcinogenic properties, etc. This work aims to assess the use of thiohydantoin as a potential antitumor agent against MCF-7 breast cancer cells. Methods: MTT and neutral red assays were used to assess the possible cytotoxic activity of compounds against MCF-7 cells. Cell volume measurement and analysis were performed by flow cytometry. Fluorescence analysis was carried out to determine patterns of cell death induced by thiohydantoins. Results: The treatment with micromolar doses of thiohydantoins promoted a decrease in the viability of MCF-7 breast tumor cells. An increase in the ROS and NO production, reduction in cell volume, loss of membrane integrity, mitochondrial depolarization, and increased fluorescence for annexin-V and caspase-3 were also observed. These findings indicate cell death by apoptosis and increased autophagic vacuoles, stopping the cell cycle in the G1/ G0 phase. Conclusion: Our results indicate that thiohydantoins are cytotoxic to breast tumor cells, and this effect is linked to the increase in ROS production. This phenomenon changes tumorigenic pathways, which halt the cell cycle in G1/G0. This is an essential checkpoint for DNA errors, which may have altered how cells produce energy, causing a decrease in mitochondrial viability and thus leading to the apoptotic process. Furthermore, the results indicate increased autophagy, a vital process linked to a decrease in lysosomal viability and thus considered a cell death and tumor suppression mechanism.

Background: Bowl or colorectal cancer (CRC) is the third most common type of cancer with about two million new cases every year. CRC is the second leading cause of cancer related mortalities. Objective: The study aims to evaluate the anticancer activity of ethanolic Ginger Extract (GE) in HCT-116 colon cells and colorectal tumors induced by dimethylhydrazine (DMH). Methods: The antiproliferative activity was measured by MTT assay and the gene expression was assessed by q-RTPCR. For the antitumor study, rats were divided into five groups in random; control, group two was orally treated with 300 mg/kg of GE for 21 weeks, group three was s.c. injected with DMH (20 mg/kg) for 9 weeks, and groups four and five were treated with DMH and then treated with cisplatin (2.5 mg/kg, i.p) or GE, respectively, for 21 weeks. Results: GE had a significant antiproliferative activity with IC50~ 12.5 μg/ml. GE induced both extrinsic and intrinsic apoptotic pathways. GE induced the expression of FasL, TRAIL, p53, and caspase-8 and downregulated Bcl-2 and survivin genes. Treatment of rats with DMH resulted in 100% tumor incidence and 2.3 tumors/rat. DMH significantly elevated the serum ALT, urea, and creatinine and significantly decreased the body weight gain. DMH also caused significant reductions in the hepatic GSH level, and the activities of catalase, SOD, GST, and GR in the liver as well as the renal GSH content and γ-GT activity. The colon from rats insulted with DMH showed adenomatous polyps with polymorphism and mitosis. The mucosa and submucosa were infested with inflammatory cells while serosa and muscularis were devoid from these cells. However, the muscularis was infiltrated with cystic formation, anaplastic changes, and hemorrhage. GE was able to alleviate all the previous deleterious effects of DMH and it was superior to cisplatin in its ameliorative effects. It did so without eliciting hepatotoxicity or nephrotoxicity which were shown in the group treated with DMH and cisplatin. Conclusion: This study proved that the antitumor activity of GE against the DMH induced-CRC is superior to cisplatin. GE was also safer than cisplatin and did not elicit hepatotoxicity or nephrotoxicity. GE induced apoptosis and has carcinostatic activity.

Background: Chronic inflammation plays a crucial role in the initiation, promotion, and invasion of tumors, and thus the antiproliferative effects of numerous anti-inflammatory drugs have been frequently reported in the literature. Upregulation of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) has been linked to various human cancers, including breast cancer. Objectives: This research aims to investigate the antiproliferative activity of different Non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 selective and non-selective agents, against various breast cancer cell lines and to elucidate possible molecular pathways involved in their activity. Methods: The antiproliferative and combined effects of NSAIDs with raloxifene were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. A mass spectrometry-based targeted metabolomics approach was used to profile the metabolomic changes induced in the T47d cells upon drug treatment. Results: Our results have demonstrated that celecoxib, a potent and selective COX-2 inhibitor, resulted in significant antiproliferative activity against all examined breast cancer cell lines with IC50 values of 95.44, 49.50. and 97.70 μM against MDA-MB-231, T47d, and MCF-7, respectively. Additionally, celecoxib exhibited a synergistic effect against T47d cells combined with raloxifene, a selective estrogen receptor modulator. Interestingly, celecoxib treatment increased cell apoptosis and resulted in substantial inhibition of cancer cell migration. In addition, the metabolomic analysis suggests that celecoxib may have affected metabolites (n = 43) that are involved in several pathways, including the tricarboxylic acid cycle, amino acids metabolism pathways, and energy production pathways in cancer cells. Conclusion: Celecoxib may possess potential therapeutic utility for breast cancer treatment as monotherapy or in combination therapy. The reported metabolic changes taking place upon celecoxib treatment may shed light on possible molecular targets mediating the antiproliferative activity of celecoxib in an independent manner of its COX-2 inhibition.

Background: In Malawi, cancer is one of the leading causes of morbidity and mortality. This has led to increased use of herbal medicines for cancer management. Objective: This study aimed at identifying medicinal plants that are used for the management of cancer in the southern area of Karonga district, Northern Malawi. Methods: Semi-structured individual questionnaire interviews were used to collect ethnobotanical data from traditional herbal practitioners in the study area. Results: A total of twenty six (26) plant species from seventeen (17) botanical families were reported by Traditional Herbal Practitioners to be effective in the management of cancer. The botanical families with representation of more than one plant species were Fabaceae with five species, followed by Combretaceae and the Anacardiaceae with three species each, and Meliaceaewith with two species. The relative frequency of citation (RFC) showed that Senna singueana (RFC = 0.833), Lannea discolour (RFC = 0.833), Melia azedarach (RFC = 0.667), and Moringa oleifera (RFC = 0.667) were the medicinal plant species which were frequently mentioned and used in the study. The recipes could be a mixture of plant species or plant parts such as the leaves, barks, roots, rhizomes, seeds, flowers, and fruits. Conclusion: The study showed that a potential cancer management drug could be developed from the medicinal plant species found in the area. The results of this study could provide baseline information on medicinal plant species for further phytochemical studies and other studies to validate their use.