Anti-Cancer Agents in Medicinal Chemistry - Volume 20, Issue 17, 2020

Background: Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer. Methods: Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: ‘aromatase’, ‘aromatase inhibitors’, ‘breast cancer’, ‘steroidal aromatase inhibitors’, ‘non-steroidal inhibitors’ and ‘generations of aromatase inhibitors’. Results: In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment. Conclusion: AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.

Angiogenesis, generation of novel blood vessels from pre-existing ones, is a prerequisite for the physiological expansion, reparation, and functioning of body tissues and systems. However, it is also involved in some pathological inflammatory situations, such as oncologic and chronic degenerative disorders. The correct angiogenesis and neo-vascular response also accompanies wound healing, interaction with biocompatible materials, and tissue regeneration. In this respect, natural products deriving from terrestrial and marine plants/organisms may prevent and even cure various angiogenesis-dependent disorders. Bioactive natural compounds with antioxidant and anti-inflammatory activities could concur to maintain adequate vascularization and endothelial functions and inhibit angiogenesis, thus controlling tumor development. This review aims to illustrate the role of some marine-derived compounds as anti-angiogenetic agents.

Background: Recently, the application of cancer nanotechnology-based drug delivery to cancer cells has arisen as an important method to resolve multiple molecular, biophysical, and biochemical obstacles, which the body is preparing to resist against the productive implementation of chemotherapeutic medications. Drug delivery technologies focused on nanoparticles, which have resolved some of the drawbacks of conventional chemotherapy as, decreased drug viscosity, chemo-resistance, precise malignity, limited medicative measures with low oral bioactivity. Due to their adjustable size and surface properties, the half-life period of a drug can be increased in the bloodstream. Objective: The aim of the current study is to collect and document the data available on the drug delivery system for anticancer drugs. The present study includes some of the drug carriers like liposomes, carbon dots, micelles, carbon nanotubes, magnetic nanoparticles, etc. Methods: To write this review, an exhaustive literature survey was carried out using relevant work published in various SCI, Scopus, and non-SCI indexed journals. The different search engines used to download the research/ review papers are Google search, PubMed, Science Direct, Google Scholar, Scientific Information Database and Research Gate, etc. Results: Nanotechnology offers better pharmacokinetics, reduces the systematic toxicities related to the chemotherapies and a better route of drug administration. In the analysis, we critically highlight recent studies on carcinoma-fighting nanotechnology. Conclusion: In the present study, different kinds of nano-based drug delivery systems have been discussed along with their characteristic features, the encapsulation of anticancer agents into different types of nanometresized vehicles and their general mechanism.

Cancer is one of the most leading causes of death worldwide. It is one of the primary global diseases that cause morbidity and mortality in millions of people. It is usually caused by different carcinogenic agents that damage the genetic material and alter the cell signaling pathways. Carcinogens are classified into two groups as genotoxic and non-genotoxic agents. Genotoxic carcinogens are capable of directly altering the genetic material, while the non-genotoxic carcinogens are capable of producing cancer by some secondary mechanisms not related to direct gene damage. There is undoubtedly the greatest need to utilize some novel natural products as anticancer agents, as these are within reach everywhere. Interventions by some natural products aimed at decreasing the levels and conditions of these risk factors can reduce the frequency of cancer incidences. Cancer is conventionally treated by surgery, radiation therapy and chemotherapy, but such treatments may be fast-acting and causes adverse effects on normal tissues. Alternative and innovative methods of cancer treatment with the least side effects and improved efficiency are being encouraged. In this review, we discuss the different risk factors of cancer development, conventional and innovative strategies of its management and provide a brief review of the most recognized natural products used as anticancer agents globally.

Background and Purpose: This study subjected a rat model to the extracts of muscle and shell tissues from Portunus segnis to assess their therapeutic effects on the HT-29 colon cancer cells as well as on colonic Aberrant Crypt Foci (ACF) induced by Azoxymethane (AOM). Methods: The cell line was exposed to the extracts to compare the cytotoxicity of hexane, butanol, ethyl acetate, and water extract of muscle and ethanolic extract of the shell. Male rats (n=40) were assigned into control, positive, negative, and treatment groups. The animals were injected with AOM, except the control group, and then exposed to 250 and 500mg/kg of the crude extracts. Immunohistochemical localization of Bax and Bcl-2, as well as ACF and antioxidant enzymes, were evaluated in the rat colon. Results: The butanolic muscle extract and ethanolic shell one demonstrated an IC50 of 9.02±0.19μg/ml and 20.23±0.27μg/ml towards the cell line, respectively. Dietary exposure inhibited the ACF formation and crypt multiplicity in the colon compared to the cancer control group. The activity of SOD and CAT increased, while that of MDA decreased. The expression of Bax and Bcl-2 increased and decreased, respectively. Conclusion: Taken together, the results show that both extractions were suggested to be suppressive to AOMinduced colon cancer.

Background: The incidence and mortality of breast cancer are increasing annually. Breast cancer seriously threatens women's health and quality of life. We aimed to measure the clinical value of CPN1, a new serum marker of breast cancer and to evaluate the efficacy of CPN1 in combination with CA15-3. Methods: Seventy samples of breast cancer with lymph node metastasis, seventy-three samples of nonmetastatic breast cancer and twenty-five samples of healthy human serum were collected. Serum CA15-3 concentration was determined by Roche Elecsys, and serum CPN1 concentration was determined by ELISA. Results: In breast cancer patients, serum CPN1 concentration was positively correlated with tumour size, clinical stage and CA15-3 concentration (r = 0.376, P<0.0001). ROC curve analysis showed that the optimal critical concentration of CPN1 for breast cancer diagnosis was 32.8pg/ml. The optimal critical concentration of CPN1 in the diagnosis of metastatic breast cancer was 66.121pg/ml. CPN1 has a greater diagnostic ability for breast cancer (AUCCA15-3=0.702 vs. AUCCPN1=0.886, P<0.0001) and metastatic breast cancer (AUCCA15-3=0.629 vs. AUCCPN1=0.887, P<0.0001) than CA15-3, and the combined detection of CA15-3 and CPN1 can improve the diagnostic efficiency for breast cancer (AUCCA15-3+CPN1=0.916) and for distinguishing between metastatic and non-metastatic breast cancer (AUCCA15-3+CPN1=0.895). Conclusion: CPN1 can be used as a new tumour marker to diagnose and evaluate the invasion and metastasis of breast cancer. The combined detection of CPN1 and CA15-3 is more accurate and has a certain value in clinical application.

Background: Nowadays, the biological properties and anticancer activities of platinum-based drugs and metal coordination complexes have been receiving particular attention. These compounds have revealed clinical potential in cancer chemotherapy. Objective: In this research, two binuclear platinum complexes including [Pt2Cl2(bhq)2(μ-dppm)] (1) and [(p- MeC6H4)(bhq) Pt(μ-dppm)Pt(bhq)(CF3CO2)] (2) with bhq: benzo[h] quinolone and dppm: bis(diphenylphosphino) methane have been synthesized and evaluated for their anticancer activity against A2780 and A2780/RCIS cancer cell lines. Methods: The DNA binding and interaction of AMP/GMP nucleotide with these complexes were explored by several experimental and theoretical methods, including UV-Visible, fluorescence spectroscopic techniques and docking analysis. These complexes have demonstrated significant anticancer properties against cisplatinsensitive (A2780) and cisplatin-resistant (A2780/RCIS) human ovarian cancer cell lines. Results: The obtained results indicated that these complexes interact with DNA. Additionally, the fluorescence emission measurements indicated that the platinum complexes binding with DNA structure occurs through nonintercalative interaction. The molecular docking assessments have also revealed the binding of these platinum complexes through DNA grooves. Moreover, the results have indicated that complex 1 exhibited more anticancer activity than complex 2. Conclusion: The results of the DNA binding with these platinum complexes confirmed their potential antitumor properties. The substitution of -C6H4CH3 and -CO2CF3 groups in complex 2 with two chlorine atoms in complex 1 acquired the significant improvement of the anticancer activity against the cancer cell.

Background: Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy. MYC family oncogenes are amplified and overexpressed in 20% of SCLCs, showing that MYC oncogenes and MYC regulated genes are strong candidates as therapeutic targets for SCLC. c-MYC plays a fundamental role in cancer stem cell properties and malignant transformation. Several targets have been identified by the activation/repression of MYC. Deregulated expression levels of lncRNAs have also been observed in many cancers. Objective: The aim of the present study is to investigate the lncRNA profiles which depend on MYC expression levels in SCLC. Methods: Firstly, we constructed lentiviral vectors for MYC overexpression/inhibition. MYC expression is suppressed by lentiviral shRNA vector in MYC amplified H82 and N417 cells, and overexpressed by lentiviral inducible overexpression vector in MYC non-amplified H345 cells. LncRNA cDNA is transcribed from total RNA samples, and 91 lncRNAs are evaluated by qRT-PCR. Results: We observed that N417, H82 and H345 cells require MYC for their growth. Besides, MYC is not only found to regulate the expressions of genes related to invasion, stem cell properties, apoptosis and cell cycle (p21, Bcl2, cyclinD1, Sox2, Aldh1a1, and N-Cadherin), but also found to regulate lncRNAs. With this respect, expressions of AK23948, ANRIL, E2F4AS, GAS5, MEG3, H19, L1PA16, SFMBT2, ZEB2NAT, HOTAIR, Sox2OT, PVT1, and BC200 were observed to be in parallel with MYC expression, whereas expressions of Malat1, PTENP1, Neat1, UCA1, SNHG3, and SNHG6 were inversely correlated. Conclusion: Targeting MYC-regulated genes as a therapeutic strategy can be important for SCLC therapy. This study indicated the importance of identifying MYC-regulated lncRNAs and that these can be utilized to develop a therapeutic strategy for SCLC.

Background: Glioma is the most common tumor of the central nervous system. Hericium erinaceus, which has been reported to have a variety of pharmacological activities, is a widely used Traditional Chinese Medicine (TCM), and also a kind of delicious food accepted by the public. Methods and Results: In this study, two new natural products, compounds 1 and 2, were isolated and identified from Hericium erinaceus. They were named erinacerin O and erinacerin P, respectively, after the structural identification, and their effects on human glioma cell line U87 were evaluated. Erinacerin P (2) exhibited obvious cytotoxicity on human glioma cell line U87. The IC50 value of 2 was 19.32μg/mL. The results showed that the apoptosis of U87 cells treated with 2 increased and the morphology of U87 cells altered significantly. Flow cytometry experiment showed that 2 could significantly increase the apoptosis rate of U87 cells and reduce DNA replication. Western blot results suggested the Bax/capase-3 pathway was involved in the U87 cell apoptosis induced by 2. Conclusion: Erinacerin O and Erinacerin P are novel compounds obtained from Hericium erinaceus and Erinacerin P could be a potential novel glioma inhibitor.

Background: The natural products constitute an important source of antitumor and cytotoxic agents. Naphthoquinones are effectively quinones present in different plants, with demonstrated anticancer activities. A recent study conducted by our group demonstrated the antileukemic potential of two novel triazol-1,4- naphthoquinones derivatives, PTN (2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1,4-naphthoquinone) and MPTN (2-[4- (4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1,4-naphthoquinone). Although, the mechanisms underlying the proapoptotic effects of PTN and MPTN have not been fully elucidated so far. Objective: The aim of this study was to evaluate the proapoptotic mechanism of PTN and MPTN in human acute leukemia cells. Methods: We used fluorescence microscopy to observe acridine orange and annexin V staining cells. Flow cytometry assay has also been used for ROS quantification, BAX and cytochrome c proteins expression and apoptosis analysis. MTT assay and western blotting technique have been performed as well for MAPK pathway analysis. Results: By using the acridine orange and annexin V staining with fluorescence microscopy, we have characterized the proapoptotic effects of PTN and MPTN in HL-60 cells involving the intrinsic mitochondrial pathway, since these compounds promoted an increase in the intracellular BAX and cytochrome c protein levels (p<0.05). We further demonstrated that apoptosis induction in HL-60 cells was mediated by increasing intracellular ROS levels via ERK but not p38 MAPKs pathway. Conclusion: Taken together, these results have demonstrated that PTN and MPTN are promising tools for the development of new anti-leukemic drugs.

Background: Melanoma causes more than 80% of deaths from all dermatologic cancers. Hence, screening and identifying effective compounds to inhibit the growth of melanoma have crucial importance in basic and clinical treatment. Methods: High throughput screening was performed to screen and identify compounds that have anti-melanoma ability. Melanoma cell and mouse allograft models were used to examine the anti-tumor effects of Nuciferine (NCFR). Western blot, qPCR, and lentivirus overexpression were applied to detect the activation of the TLR4/NF-ΚB signaling pathway. Results: NCFR administration significantly suppressed melanoma cell growth and tumor size by inhibiting the phosphorylation of p65. NCFR treatment also could suppress TNF-α-induced activation of NF-ΚB signaling. The anti-tumor effect of NCFR might be mediated by targeting Toll-like receptors 4. Conclusion: NCFR inhibits melanoma cell growth and suppresses tumor size, which provides potential therapeutic strategies for melanoma treatment.

Aims: To identify variables having a critical role in prostate cancer patients experiencing osteometastasis. Background: Prostatic carcinoma is a multifactorial complex disorder that exhibits an increased propensity to develop bone metastasis. An interplay of inflammatory and bone remodeling parameters promotes the formation of pre-metastatic niches in bones of patients, which could render them more vulnerable to skeletal disabilities. Objective: To evaluate the multi-dynamic inter-relationship of circulating variables in prostate cancer patients experiencing osteo-metastasis. Materials and Methods: Fifty-seven (n=57) men with clinically confirmed prostate cancer, fifty-nine (n=59) with skeletal metastases, and one hundred (n=100) healthy subjects i.e., men aging from 53-84 years with no clinical evidence of prostate were recruited from the Jinnah Hospital Lahore, Pakistan. Informed consent was obtained, and a venous blood sample was drawn and stored at -70oC until assayed. Levels of variables were evaluated using appropriate methods. Levels of Matrix Metalloproteinases (MMPs), Osteopontin (OPN), TGH- β, and sRANKL were estimated by the ELISA method. Each sample was suspended and the given protocol was employed. ELISA readings were obtained for the estimation of all variables. Results: Highly significant (P#130;0.05) differential expression of oxidative stress, inflammatory cytokines, and bone remodeling variables were observed in localized and osteo-metastatic CA prostate patients. A strong positive correlation was revealed among OPN, sRANKL, MMP-7, MMP-9, PSA, and TGF-β (OPN vs. MMP-7, r=0.698* and OPN vs. MMP-9, r=0.765**, OPN vs. RANKL, =0.856*, sRANKL vs. MMP-9, r=0.825**, TGF- β vs. RANKL, r=0.868* and PSA vs. TGF- β, r=0.752*); lower levels of OPG were estimated in metastasized patients, showing that both osteolytic and osteoblastic phases of bone remodeling occur simultaneously. Conclusion: The altered oxidative and inflammatory responses endorse Matrix Metalloproteinases (MMPs) increased activity, RANKL/OPG imbalance, and enhanced bone matrix proteins turnover, which can foster the process of osteo-metastasis. The perturbed RANKL/OPG drift and enhanced PSA levels are associated with increased TGF-β activity to aggravate Epithelial Mesenchymal transition (EM) and osteo-tropism of prostate cancer. Thus, designing novel targets of these major variables can minimize the incidence of prostate cancer patients.

Background: Gastric cancer, a common malignant tumour worldwide, has a relatively poor prognosis and is a serious threat to human health. Histone Deacetylase Inhibitors (HDACi) are anticancer agents that are known to affect the cell growth of different cancer types. Trichostatin A (TSA) selectively inhibits the class I and II mammalian Histone Deacetylase (HDAC) family enzymes and regulates many cell processes. Still, the underlying mechanisms of HDACs are not fully understood in gastric cancer. Objective: This study aims to investigate the antitumor effect and the mechanism of growth modulation of gastric cancer cells by TSA. Methods: The cell proliferation of gastric cancer cells was measured by MTT and BrdU immunofluorescence assays. Soft agar assay was used to detect the colony formation ability of gastric cancer cells. Flow cytometry was used to examine cell cycle and apoptosis. Western blot was employed to detect protein expression of target factors. Results: TSA inhibits the proliferation of MKN-45 and SGC-7901 cells and leads to significant repression of colony number and size. Flow cytometry assays show TSA induces cell cycle arrest at G1 phase and apoptosis, and TSA effects the expression of related factors in the mitochondrial apoptotic signalling and cell cycle-related regulatory pathways. Furthermore, TSA increased histone H3K27 acetylation and downregulated the expression of PI3K and p-AKT. Conclusion: Downregulating PI3K/AKT pathway activation is involved in TSA-mediated proliferation inhibition of gastric cancer.

Background: Persistent infection with the high-risk of human papillomavirus (HR-HPVs) is the primary etiological factor of cervical cancer; HR-HPVs express oncoproteins E6 and E7, both of which play key roles in the progression of cervical carcinogenesis. Zinc Finger Nucleases (ZFNs) targeting HPV E7 induce specific shear of the E7 gene, weakening the malignant biological effects, hence showing great potential for clinical transformation. Objective: Our aim was to develop a new comprehensive therapy for better clinical application of ZFNs. We here explored the anti-cancer efficiency of HPV targeted ZFNs combined with a platinum-based antineoplastic drug Cisplatin (DDP) and an HDAC inhibitor Trichostatin A (TSA). Methods: SiHa and HeLa cells were exposed to different concentrations of DDP and TSA; the appropriate concentrations for the following experiments were screened according to cell apoptosis. Then cells were grouped for combined or separate treatments; apoptosis, cell viability and proliferation ability were measured by flow cytometry detection, CCK-8 assays and colony formation assays. The xenograft experiments were also performed to determine the anti-cancer effects of the combined therapy. In addition, the HPV E7 and RB1 expressions were measured by western blot analysis. Results: Results showed that the combined therapy induced about two times more apoptosis than that of ZFNs alone in SiHa and HeLa cells, and much more inhibition of cell viability than either of the separate treatment. The colony formation ability was inhibited more than 80% by the co-treatment, the protein expression of HPV16/18E7 was down regulated and that of RB1 was elevated. In addition, the xenografts experiment showed a synergistic effect between DDP and TSA together with ZFNs. Conclusion: Our results demonstrated that ZFNs combined with DDP or TSA functioned effectively in cervical cancer cells, and it provided novel ideas for the prevention and treatment of HPV-related cervical malignancies.