Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 17, 2022

Currently, chemotherapy is still the main strategy for cancer treatment. However, chemotherapy resistance remains a challenge. Disulfiram (DSF) is an FDA-approved medicine for the treatment of alcoholism; however, it was later revealed to have anticancer properties. Importantly, numerous studies have shown that DSF can be employed as a chemotherapeutic sensitizer to enhance the anticancer efficacy of chemo-drugs in a variety of cancers. Furthermore, the combinations of DSF and chemo-drugs have been tested in clinical trials. In the review, we summarized the possible molecular targets and mechanisms of DSF to reverse chemo-resistance. We also further discussed the opportunities and challenges of DSF as a chemo-therapeutic sensitizer. In conclusion, DSF could be a potentially repurposed drug that sensitizes cancer cells to chemotherapy in the clinic.

Gastric cancer (GC) is the fifth most common type of tumor and the third leading cause of cancer death worldwide. The evolution of gastric carcinogenesis is still poorly understood and, for this reason, preclinical research protocols were established that included the development of gastric cancer cell lines and the establishment of models of gastric carcinogenesis in non-human primates such as Sapajus apella. A comprehensive literature search was performed in relevant databases such as PubMed, ResearchGate, and Google Scholar to identify studies related to the topic. After an in-depth study of these reports, significant data were collected and compiled under appropriate headings. The main result of the studies carried out by the group on GC is the demonstration of the MYC gene overexpression as a common phenomenon in stomach carcinogenesis. Furthermore, we revealed that reducing the expression of the CDC25B gene, regulated by the MYC protein, is a therapeutic strategy against stomach tumors. This review article reveals preclinical evidence that treatment with menadione in experimental models of gastric tumorigenesis, in vivo and in vitro, inhibits the action of the phosphatase CDC25B and, consequently, prevents cell proliferation, invasion, and migration.

Chronic myeloid leukemia (CML) is a blood cancer predominantly affecting older adult patients. According to the American Cancer Society, an estimated 8,860 people will be diagnosed with CML in 2022. Treatments for CML have evolved with a focus on CML phase severity or progression. Overall, there have been some breakthrough treatment options for a high percentage of patients with CML. This is largely due to the discovery of tyrosine kinase inhibitors (TKI); however, drug resistance continues to present a significant challenge in the management of CML disease. The use of interferon (IFN), antimetabolites, and bone marrow transplants provides alternative treatment options, but also presents limitations, including severe side effects, toxicity, and graft versus host disease. Nanomedicine has demonstrated benefits in terms of efficacy, often reducing or eliminating unwanted toxicities associated with the use of conventional drug agents. This review summarizes rational molecular targets of CML drugs and provides highlights of current FDA-approved agents for the treatment of CML. Additionally, this communication includes an overview of the limitations of conventional treatments and how nanomedicine has addressed challenges encountered during CML treatment.

The thiazolopyrimidine nucleus is a bioisosteric analog of purine and an important class of N-containing heterocycles. Thiazolopyrimidine scaffolds are considered a promising class of bioactive compounds that encompass diverse biological activities, such as antibacterial, antiviral, antifungal, anticancer, corticotrophin-releasing factor antagonists, anti-inflammatory, antituberculosis, and glutamic receptors antagonists. Despite the importance of thiazolopyrimidines from a pharmacological viewpoint, there is hardly a comprehensive review on this important heterocyclic nucleus. Throughout the years, those scaffolds have been studied extensively for its anticancer properties and several compounds were designed, synthesized, and evaluated for their anticancer effects with activity in the μM to nM range. However, there are hardly any reviews covering the anticancer effects of thiazolopyrimidines. In this review, an effort was made to compile literature covering the anticancer activity of thiazolopyrimidines reported in the last decade (2010-2020). Nearly thirty articles were reviewed and compounds with IC50 < 50 μM against at least 50% of the used cell lines were listed in this review. The best ten compounds (10a, 14b, 17g, 18, 25e, 25k, 34e, 41i, 49a and 49c) showing the best anticancer activity against the corresponding cell lines during the last 10 years are highlighted. By highlighting the most active compounds, this review article sheds light on the structural features associated with the strongest anticancer effects to provide guidance for future research aiming to develop anticancer molecules.

Collagen is the most important structural protein and also the main component of the extra-cellular matrix (ECM). It plays a role in tumor progression. Collagen can be regulated by altering its biosynthesis pathway through various signaling pathways, receptors, and genes. The activity of cancer cells can also be regulated by other ECM components like metalloproteinases, hyaluronic acid, fibronectin, and so on. Hypoxia is also one of the conditions that lead to cancer progression by stimulating the expression of procollagen lysine as a collagen crosslinker, which increases the size of collagen fibres promoting cancer spread. The collagen content in cancerous cells leads to resistance to chemotherapy. So, to reduce this resistance, some collagen-regulating therapies are introduced, including inhibiting its biosynthesis, disturbing cancer cell signaling pathway, mediating ECM components, and directly utilizing collagenase. This study is an effort to compile the strategies reported to control the collagen level and different collagen inhibitors reported so far. More research is needed in this area. Growing understanding of collagen’s structural features and its role in cancer progression will aid in the advancement of newer chemotherapies.

Background: Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to cancer treatment. The interaction between a photosensitizer (PS), ideal wavelength radiation, and tissue molecular oxygen triggers a series of photochemical reactions responsible for producing reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells. Objective: Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near-infrared radiation in tumor models. Methods: A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, 25 eligible articles were included in this systematic review using inclusion, exclusion, and eligibility criteria. Results: CUR, whether in its free state, associated with metal complexes or other PS and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters. Conclusion: The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.

Background: Artabotrys odoratissimus (Annonaceae) is a medicinal and ornamental plant widely cultivated in Southeast Asia for its famous ylang ylang essential oil. The fruits of this plant are used for health benefits, but very little is studied about the bioactive principles, their role in regulating oxidative stress and tumour progression. Objective: The study aimed to evaluate the antiproliferative effects of fruit extract of Artabotrys odoratissimus and its bioactive fraction using cell-based assays. Methods: The free radical scavenging and antiproliferative effects of Artabotrys odoratissimus fruit ethyl acetate (FEA) extract and its bioactive fraction were evaluated using cell viability assays, colony formation assay, double staining assay, reactive oxygen species (ROS) assay, comet assay, cell cycle analysis, and western blotting. Results: The extract showed phenolic content of 149.8±0.11μg/mg Gallic acid equivalents and flavonoid content of 214.47±4.18 μg/mg Quercetin. FEA showed an IC50 value of 76.35 μg/ml in the ABTS assay and an IC50 value of 134.3±7.8 μg/ml on MIA PaCa-2 cells. The cells treated with 125 μg/ml and 250 μg/ml FEA showed increased apoptotic cells in Double staining assay, DNA damage during comet assay, enhanced ROS, and cell cycle arrest at G2M phase at 125 μg/ml and 250 μg/ml. The active fraction AF5 showed an IC50 value of 67±1.26 μg/ml on MIA PaCa-2 cells during MTT assay, displayed potential antiproliferative effects, and showed a marked increase in the expression of γH2AX and p53. Conclusion: These results prove that the fruit extract and the bioactive fraction demonstrate oxidative stress-mediated DNA damage, leading to apoptosis in the MIA PaCa-2 cell line.

Background: GRPR is over-expressed in cancer cells and is a potential drug target for the treatment of cancer. PD176252, as the most representative non-peptide inhibitor of GRPR, can inhibit the growth of cancer cells, but its low selectivity to cancer cells and normal cells limits its further application. Objective: The aim of this study was to design and synthesize novel GRPR inhibitor with stronger anti-cancer activity and higher affinity with GRPR than the lead compound PD176252. Methods: A series of 1, 3, 4-oxadiazole derivatives as PD176252 analogues (4a-4j, 6a-6q) were synthesized and their cytotoxic activity was investigated on four cancer lines with high expression of GRPR (gastric (HGC-27), colon (HCT- 116), prostate (PC-3), and lung (A549)) and one human cell line (gastric mucosal epithelial (GES-1)) by MTT assay. Flow cytometry analysis and Western Blot were used to determine whether the compound induced programmed apoptosis of cancer cells. Competitive binding experiment was used to verify the affinity between GRPR and the optimal compound. Results: Compound 6m exhibited significant growth inhibition on all tested cancer cell lines, especially gastric cancer cells (HGC-27 cellular IC50 0.37 ± 0.04μM). Also, the selectivity of 6m to HGC-27 was much higher than that of PD176252. Flow cytometric analysis and Western Blot proved that 6m significantly promoted the apoptosis of HGC- 27 cells. Moreover, competitive binding experiment confirmed the close binding of 6m with GRPR, which indicated 6m with a higher affinity than lead compound PD176252. Conclusion: Our results suggested that 6m, as a novel GRPR inhibitor, had a higher affinity with GRPR and potential anti-cancer effect than PD176252, which can be used as a template for further optimization.

Background: DNA Topoisomerase II Alpha (TOP2A), a protein-coding gene, is central to the replication process and has been found deregulated in several malignancies, including breast cancer. Several therapeutic regimens have been developed and approved for targeting TOP2A and have prolonged the survival of cancer patients. However, due to the inherent nature of the tumor cell to evolve, the earlier positive response turns into a refractory chemoresistance in breast cancer patients. Objective: The study’s main objective was to analyze the expression pattern and prognostic significance of TOP2A in breast cancer patients and screen new therapeutic molecules targeting TOP2A. Methods: We utilized an integrated bioinformatic approach to analyze the expression pattern, genetic alteration, immune association, and prognostic significance of TOP2A in breast cancer (BC) and screened natural compounds targeting TOP2A, and performed an in silico and an in vitro analysis. Results: Our study showed that TOP2A is highly overexpressed in breast cancer tissues and overexpression of TOP2A correlates with worse overall survival (OS) and relapse-free survival (RFS). Moreover, TOP2A showed a high association with tumor stroma, particularly with myeloid-derived suppressor cells. Also, in silico and in vitro analysis revealed cryptolepine as a promising natural compound targeting TOP2A. Conclusion: Cumulatively, this study signifies that TOP2A promotes breast cancer progression, and targeting TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance.

Background: Triple-negative breast cancer is challenging to treat due to its heterogeneity and lack of therapeutic targets. Hence, systemic chemotherapy is still the mainstay in TNBC treatment. Unfortunately, patients commonly develop chemoresistance. Androgen signalling through its receptor is an essential player in breast cancer, where it has been shown to confer chemoresistance to TNBC cells. Objective: The objective of the study was to elucidate the mechanistic effects of enzalutamide in the chemoresponse of TNBC cells to doxorubicin through the apoptosis pathway. Methods: MDA-MB-231 and MDA-MB-453 cells were used as model systems of TNBC. Cell viability and apoptosis were investigated upon treatment of cells with doxorubicin in the presence of dihydrotestosterone (DHT) and/or enzalutamide. Caspase 3/7 activity and TUNEL assays were performed to assess the induction of apoptosis. The expression of apoptosis-regulatory genes was assayed by qPCR for the detection of expression changes. Results: Enzalutamide decreased the viability of MDA-MB-231 and MDA-MB- 453 cells and reduced DHT-induced chemoresistance of both cell lines. It also increased the chemosensitivity towards doxorubicin in MDA-MB-231 cells. Increasing DNA degradation and caspase 3/7 activity were concomitant with these outcomes. Moreover, enzalutamide downregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in MDA-MB-231 cells, while increasing the expression of the pro-apoptotic gene bid. On the other hand, DHT upregulated the expression of the anti-apoptosis genes, mcl1 and bcl2, in both cell lines. Conclusion: DHT increased the expression of the anti-apoptosis genes mcl1 and bcl2 in the TNBC cells, presumably leading to cell survival via the prevention of doxorubicin-induced apoptosis. On the other hand, enzalutamide may sensitize the cells to doxorubicin through downregulation of the bid/bcl2/mcl1 axis that normally activates the executive caspases, caspase 3/7. The activities of the latter enzymes were apparent in DNA degradation at the late stages of apoptosis.