Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 3, 2022

Background: Breast Cancer (BC) is the most widely occurring disease in women. A massive number of women are diagnosed with breast cancer, and many lose their lives every year. Cancer is the leading cause of death worldwide, posing a formidable challenge to the current medication difficulties. Objectives: The main objective of this study is to examine and explore novel therapy (PROTAC) and its effectiveness against breast cancer. Methods: The literature search was conducted across Medline, Cochrane, ScienceDirect, Wiley Online, Google Scholar, PubMed, and Bentham Sciences from 2001 to 2020. The articles collected were screened, segregated, and selected papers were included for writing the review article. Results and Conclusion: A novel innovation emerged around two decades ago that has great potential to overcome the limitations and provide future direction for the treatment of many diseases, which has presently not many therapeutic options available and are regarded as incurable with traditional techniques. That innovation is called PROTAC (Proteolysis Targeting Chimera), which can efficaciously ubiquitinate and debase cancer, encouraging proteins through noncovalent interaction. PROTACs constituted of two active regions isolated by a linker are equipped for eliminating explicit undesirable protein. It is empowering greater sensitivity to "drugresistant targets" and a more prominent opportunity to influence non-enzymatic function. PROTACs have been demonstrated to show better target selectivity contrasted with traditional small-molecule inhibitors. So far, the most investigation into PROTACs mainly concentrated on cancer treatment applications, including breast cancer. The treatment of different ailments may benefit the patients from this blossoming innovation.

Abstract: The overwhelming global burden of cancer has posed numerous challenges and opportunities for developing anti-cancer therapies. Phytochemicals have emerged as promising synergistic compounds with potential anti-cancer effects to supplement chemo- and immune-therapeutic regimens. Anti cancer synergistic effects have been investigated in the interaction between phytocompounds derived from flavonoids such as quercetin, apigenin, kaempferol, hesperidin, emodin, etc., and conventional drugs. Xanthohumol is one of the prenylated phytoflavonoid that has demonstrated key anti-cancer activities in in vitro (anti proliferation of cancer cell lines) and in vivo (animal models of xenograft tumours) studies, and has been explored from different dimensions for targeting cancer subtypes. In the last decade, xanthohumol has been investigated how it induces the anti- cancer effects at cellular and molecular levels. The different signalling cascades and targets of xanthohumol are summarized in this review. Overall, this review summarizes the current advances made in the field of natural compounds with special reference to xanthohumol and its promising anti-cancer effects to inhibit tumour progression. The present review has also discussedthe potential of xanthohumol transitioning into a leadingcandidate from nano-therapy viewpoint along with the challenges which need to be addressed for extensive preclinical and clinical anti-cancer studies.

Background: The global alliance for genomics and healthcare facilities provides innovative solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention, and treatment based on patients’ genetic profiles. Advancements in “omics” techniques, next-generation sequencing, artificial intelligence, and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. Methods: Data were collected from PubMed and Google Scholar using keywords “Precision medicine,” “precision medicine and cancer,” “anticancer agents in precision medicine,” and reviewed comprehensively. Results: Personalized therapeutics, including immunotherapy and cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described, along with various hurdles identified in the successful establishment of precision therapeutics. Conclusion: This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival, and improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.

Abstract: DNA’s integrity is continuously challenged by intrinsic cellular processes and environmental agents. To overcome this genomic damage, cells have developed multiple signalling pathways collectively named as DNA Damage Response (DDR) and composed of three components: (i) sensor proteins, which detect DNA damage, (ii) mediators that relay the signal downstream and recruit the repair machinery and (iii) the repair proteins, which restore the damaged DNA. A flawed DDR and failure to repair the damage lead to the accumulation of genetic lesions and increased genomic instability, which is recognized as a hallmark of cancer. Cancer cells tend to harbor increased mutations in DDR genes and often have fewer DDR pathways than normal cells. This makes cancer cells more dependent on particular DDR pathways and thus become more susceptible to compounds inhibiting those pathways compared to normal cells, which have all the DDR pathways intact. Understanding the roles of different DDR proteins in the DNA damage response and repair pathways and the identification of their structures have paved the way for development of their inhibitors as targeted cancer therapy. In this review, we describe the major participants of various DDR pathways, their significance in carcinogenesis and focus on the inhibitors developed against several key DDR proteins.

Abstract: Cyclin-Dependent Kinases (CDKs) are the chief regulators in cell proliferation; the kinase activities are largely regulated by their interactions with CDK Inhibitors (CKIs) and Cyclins. The association of different CDKs with CDKIs and Cyclins at the cell-cycle checkpoints of different stages of mitotic cell cycle function act more likely as the molecular switches that regulate different transcriptional events required for progression through the cell cycle. A fine balance in response to extracellular and intracellular signals is highly maintained in the orchestrated function of CDKs along with Cyclins and CDKIs for normal cell proliferation. This fine-tuning in mitotic cell cycle progression sometimes gets lost due to dysregulation of CDKs. The aberrant functioning of the CDKIs is therefore studied for its contributions as a vital hallmark of cancers. It has attracted our focus to maneuver cancer therapy. Hence, several synthetic CDKIs and their crystallography-based drug design have been explained to understand their mode of action with CDKs. Since most of the synthetic drugs function by inhibiting the CDK4/6 kinases by competitively binding to their ATP binding cleft, these synthetic drugs are reported to attack the normal, healthy growing cells adjacent to the cancer cells leading to the decrease in the life span of the cancer patients. The quest for traditional natural medicines may have a great impact on the treatment of cancer. Therefore, in the present studies, a search for naturally sourced CDK inhibitors has been briefly focused. Additionally, some synthetic crystallography-based drug design has been explained to elucidate different avenues to develop better anticancer chemotherapeutics, converting natural scaffolds into inhibitors of the CDK mediated abnormal signal transduction with lesser side effects.

Abstract: Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.

Background: Triple-Negative Breast Cancer (TNBC) is the most aggressive form of Breast Cancer (BC), with high rates of metastasis and recurrence and limited treatment options. Chemotherapy and radiotherapy, for example, have several harmful side effects, and no FDA-approved therapies are currently available. Repurposing old clinically approved drugs to target various TNBC targets is a novel method that has fewer side effects and leads to successful, low-cost drug development in a shorter amount of time. Medicinal plants containing various phytoconstituents (flavonoids, alkaloids, phenols, essential oils, tannins, glycosides, lactones) play a very crucial role in combating various types of diseases and are used in the drug development process because of having lesser side effects. Objective: The present review summarizes various categories of repurposed drugs that target multiple targets of TNBC, as well as phytochemical categories that target TNBC singly or in combination with old synthetic drugs. Methods: Literature information was collected from various databases such as Pubmed, Web of Science, Scopus, and Medline to understand and clarify the role and mechanism of repurposed synthetic drugs and phytoconstituents against TNBC by using keywords like “breast cancer”, “repurposed drugs”, “TNBC” and “phytoconstituents”. Results: Various repurposed drugs and phytochemicals that target different signaling pathways and exert their cytotoxic activities on TNBC cells ultimately lead to cell apoptosis, reducing the recurrence rate and stopping the metastasis process. Conclusion: Inhibitory effects can be seen at various levels, providing information and evidence to researchers in the drug development process. As a result, more research and investigations are needed to develop better therapeutic treatment options for TNBC.

Abstract: Cancer is one of the most alarming diseases, with an estimation of 9.6 million deaths in 2018. Glioma occurs in glial cells surrounding nerve cells. The majority of the patients with gliomas have a terminal prognosis, and the ailment has significant sway on patients and their families, be it physical, psychological, or economic wellbeing. As Glioma exhibits, both intra and inter tumour heterogeneity with multidrug resistance and current therapies are ineffective. So the development of safer anti gliomas agents is the need of hour. Bioactive heterocyclic compounds, eithernatural or synthetic, are of potential interest since they have been active against different targets with a wide range of biological activities, including anticancer activities. In addition, they can cross the biological barriers and thus interfere with various signalling pathways to induce cancer cell death. All these advantages make bioactive natural compounds prospective candidates in the management of glioma. In this review, we assessed various bioactive heterocyclic compounds, such as jaceosidin, hispudlin, luteolin, silibinin, cannabidiol, tetrahydrocannabinol, didemnin B, thymoquinone, paclitaxel, doxorubicin, and cucurbitacins for their potential anti-glioma activity. Also, different kinds of chemical reactions to obtain various heterocyclic derivatives, e.g. indole, indazole, benzimidazole, benzoquinone, quinoline, quinazoline, pyrimidine, and triazine, are listed.

Background: Lung cancer is a significant health problem and accounts for one-third of the deaths worldwide. A great majority of these deaths are caused by Non-Small Cell Lung Cancer (NSCLC). Chemotherapy is the leading treatment method for NSCLC, but resistance to chemotherapeutics is an important limiting factor that reduces the treatment success of patients with NSCLC. Objective: In this study, the relationship between differentially expressed genes affecting the survival of the patients, according to the bioinformatics analyses, and the mechanism of drug resistance is investigated for nonsmall cell lung adenocarcinoma patients. Methods: Five hundred thirteen patient samples were compared with fifty-nine control samples. The employed dataset was downloaded from The Cancer Genome Atlas (TCGA) database. The information on how the drug activity altered against the expressional diversification of the genes was extracted from the NCI-60 database. Four hundred thirty-three drugs with known Mechanism of Action (MoA) were analyzed. Diversifications of the activity of these drugs related to genes were considered based on nine lung cancer cell lines virtually. The analyses were performed using R programming language, GDCRNATools, rcellminer, and Cytoscape. Results: This work analyzed the common signaling pathways and expressional alterations of the proteins in these pathways associated with survival and drug resistance in lung adenocarcinoma. Deduced computational data demonstrated that proteins of EGFR, JNK/MAPK, NF-ΚB, PI3K /AKT/mTOR, JAK/STAT, and Wnt signaling pathways were associated with the molecular mechanism of resistance to anticancer drugs in NSCLC cells. Conclusion: To understand the relationships between resistance to anticancer drugs and EGFR, JNK/MAPK, NF-ΚB, PI3K /AKT/mTOR, JAK/STAT, and Wnt signaling pathways is an important approach to design effective therapeutics for individuals with NSCLC adenocarcinoma.

Background: Cervical Intraepithelial Neoplasia (CIN) directly precedes cervical cancer, and elevated proinflammatory cytokine Interleukins (IL)-6 is implicated in CIN. Objective: As maslinic acid exhibits anti-IL-6 property, the present study sought to determine the effect of maslinic acid on CIN in vitro and in vivo using cell cultures and mouse CIN models, respectively. Methods: The dose-effect of maslinic acid on HeLa cells, a human cervical cancer cell line, was first evaluated, including cytotoxicity, IL-6 secretion, IL-6 receptor (IL-6R) expression, proliferation potential and apoptosis status. A mouse model of CIN was also established, which was then subjected to increasing doses of maslinic acid treatment, followed by assessment of serum IL-6 level, cervical expression of IL-6R, and the proliferation potential and apoptosis of cervical tissues. Results: Maslinic acid dose-dependently inhibited cell growth and proliferation potential, reduced IL-6 secretion, cervical expression of IL-6R and induced apoptosis of HeLa cells in vitro. In the CIN mouse model, serum IL-6 level and cervical expression of IL-6R were elevated, which could be repressed by maslinic acid administration dosedependently. Additionally, maslinic acid treatment in the CIN mice could also restore the otherwise increased proliferation potential and reduced apoptosis in the cervical tissues. Conclusion: Maslinic acid exhibits potent anti-IL-6 property in the CIN mouse model, and alleviates the diseaserelated abnormality in proliferation potential and apoptosis state of the cervical tissue cells, demonstrating its usefulness as a promising agent in treating CIN.

Background: Recently, a novel crosstalk between non-coding RNAs (ncRNAs) has been casted. However, this has been seldom investigated in metastatic BC (mBC). H19 and miR-486-5p role in mBC are controversial. ICAM-1 is a recently recognized metastatic engine in mBC. Natural compounds were recently found to alter ncRNAs/target circuits. Yet, Hesperitin’s modulatory role in altering such circuits has never been investigated in mBC. Objective: The aim of this study is to investigate the impact of hesperitin on miR-486-5p/H19/ICAM-1 axis. Methods: BC patients (n=20) were recruited in the study. Bioinformatic analysis was performed using different prediction softwares. MDA-MB-231 and MCF-7 cells were cultured and transfected using several oligonucleotides or treated with serial dilutions of hesperitin. RNA was extracted and gene expression analysis was performed using q-RT-PCR. ICAM-1 protein levels were assessed using human ICAM-1 Elisa Kit. Cytotoxic potential of hesperitin against normal cells was assessed by LDH assay. Several functional analysis experiments were performed such as MTT, colony forming and migration assays. Results: The study showed that miR-486-5p and H19 had paradoxical expression profiles in BC patients. miR- 486-5p mimics and H19 siRNAs repressed ICAM-1 and halted mBC hallmarks. A novel crosstalk between miR- 486-5p and H19 was observed highlighting a bi-directional relationship between them. Hesperetin restored the expression of miR-486-5p, inhibited H19 lncRNA and ICAM-1 expression and selectively regressed mBC cell aggressiveness. Conclusion: miR-486-5p and H19 are inter-connected upstream regulators for ICAM-1 building up miR-486- 5p/H19/ICAM-1 axis that has been successfully tuned in mBC cells by hesperitin.

Background: Papillary Thyroid Carcinoma (PTC) represents the most common thyroid cancer. Until recently, treatment options for PTC patients are limited. Nilotinib is the second-generation tyrosine kinase inhibitor, and has been widely used in the treatment of Chronic Myeloid Leukemia (CML). Objectives: We aimed to explore whether nilotinib is effective for the suppression PTC cancer progression and the underlying mechanisms. Methods: In this study, the three human PTC cell lines (KTC-1, BCPAP, and TPC1) were used to verify the effects of nilotinib on cell growth. The half maximal inhibitory concentration (IC50) was calculated according to the growth curve post nilotinib treatment at different concentrations. Cell counting kit-8 and colony formation analysis were used to monitor cell growth after nilotinib treatment. Cell apoptosis and autophagy related proteins and phosphorylation of PI3K/Akt/mTOR were detected by Western blotting analysis. Results: Nilotinib treatment could effectively inhibit PTC cell growth, which was accompanied by an increase in apoptosis and induction of autophagy. Mechanistically, nilotinib treatment repressed the phosphorylation of the PI3K/Akt/mTOR pathway. Conclusion: Collectively, our results demonstrated that nilotinib may display anti-tumor effect against PTC via inhibiting PI3K/Akt/mTOR pathway and inducing apoptosis and autophagy.