Anti-Cancer Agents in Medicinal Chemistry - Volume 20, Issue 6, 2020

Introduction: In the current study, a systematic search and meta-analysis were performed to evaluate the effect of prostate cancer radiotherapy on testosterone levels of patients. Methods: To illuminate the effect of radiotherapy on the testosterone level of prostate cancer patients, a systematic search was conducted in accordance with the PRISMA guideline in electronic databases of Scopus, Embase, PubMed, Web of Science, and clinical trials up to December 2018 using relevant keywords. Based on a certain set of inclusion and exclusion criteria, 12 eligible studies that had data on the testosterone level following prostate cancer radiotherapy were included in the meta-analysis. Results: According to the various techniques of prostate cancer radiotherapy, the dose values scattered to the testicular tissues ranged from 0.31 to 10 Gy. Combining the findings from 12 studies, it was found that prostate cancer radiotherapy leads to a significant reduction in the testosterone level (Weighted Mean Difference [WMD]: -51.38 ng/dL, 95% CI: -75.86, -26.90, I2=0.0%, P<0.05). Furthermore, subgroup analysis by the patient number showed a significant reduction in the testosterone level at patient number < 50 (WMD: -80.32 ng/dL, 95% CI: -125.10, -35.55, I2= 0.0%) and 50 < patient number < 100 (WMD: -46.99 ng/dL, 95% CI: - 87.15, -6.82, I2= 0.0%). Subgroup analysis based on treatment technique type revealed a significant reduction in testosterone level after conventional radiotherapy (WMD: -56.67, 95% CI: -100.45,-12.88, I2= 34.3%) and IMRT/SBRT technique (WMD: -57.42, 95% CI: -99.39, -15.46, I2= 0.0%) in comparison with the proton therapy (WMD: 0.00, 95% CI: -80.24, 80.24). Conclusion: The findings showed a significant decrease in the testosterone level of prostate cancer patients after radiotherapy compared with pre-treatment levels.

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.

Cancer commands the second highest global mortality rate and causes severe public health problems. Recent advances have been made in cancer therapy but the incidence of the disease remains high. Research on more efficient treatment methods with reduced side effects is necessary. Historically, edible plants have been used as traditional medicines for various diseases. These demonstrate the potential of natural products as sources of bioactive compounds for anticancer treatment. Anticancer properties of phytochemicals are attributed to bioactive compounds in plant extracts that suppress cancer cell proliferation and growth by inducing both cell cycle arrest and apoptosis. This review presents a summary of the molecular identification of phytochemicals with anticancer properties and details their action mechanisms and molecular targets. Moreover, the effects of the natural product on both immunomodulatory and anticancer properties are provided.

There are concerns about the increased incidence of cancer both in developing and developed countries. In spite of recent progress in cancer therapy, this disease is still one of the leading causes of death worldwide. Consequently, there have been rigorous attempts to improve cancer therapy by looking at nature as a rich source of naturally occurring anti-tumor drugs. Curcumin is a well-known plant-derived polyphenol found in turmeric. This compound has numerous pharmacological effects such as antioxidant, anti-inflammatory, antidiabetic and anti-tumor properties. Curcumin is capable of suppressing the growth of a variety of cancer cells including those of bladder cancer. Given the involvement of various signaling pathways such as PI3K, Akt, mTOR and VEGF in the progression and malignancy of bladder cancer, and considering the potential of curcumin in targeting signaling pathways, it seems that curcumin can be considered as a promising candidate in bladder cancer therapy. In the present review, we describe the molecular signaling pathways through which curcumin inhibits invasion and metastasis of bladder cancer cells.

Cancer is one of the prominent global causes of death and the foremost worldwide health concern. Despite unprecedented progress in cancer chemoprevention, a vast number of cancers, however, remain an undefeatable challenge for treatment modalities. Immense therapeutic activities of puerarin contribute to its use in various health disorders. In this review, we explored the potential molecular mechanisms and targets of puerarin, proving its potential as a novel anticancer agent, for future cancer therapy and chemoprevention. Several mechanisms account for anticancer activity of puerarin which includes downregulation of NF-kB signalling pathway, mTOR signalling pathway, PI3K and BCl-2 proteins and upregulation of miR-16, caspase proteins, c- Jun N terminal kinase and extracellular signal-regulated kinase 1/2. These alterations result in inhibition of cancer cell proliferation and/or induction of apoptosis. Understanding the molecular mechanisms involved in chemotherapy and chemoprevention could aid in the more pronounced exploration of puerarin in effective cancer treatment.

Background: LCL161, a SMAC’S small molecule mimetic, can bind to a variety of IAPs and activate Caspases. We found that on its own, LCL161induces apoptosis of drug-resistant breast cancer cells by binding to a variety of IAPs and activating Caspases. However, when LCL161 is used in combination with Caspase Inhibitors (CI), its capacity to induce apoptosis of breast cancer cells is enhanced. Objective: To carry out proteomic and bioinformatics analysis of LCL161 in combination with CI. We aim to identify the key proteins and mechanisms of breast cancer drug-resistant apoptosis, thereby aiding in the breast cancer drug resistance treatment and identification of drug targeting markers. Methods: Cell culture experiments were carried out to explore the effect of LCL161 combined with CI on the proliferation of breast cancer drug-resistant cells. Proteomic analysis was carried out to determine the protein expression differences between breast cancer drug-resistant cells and LCL161 combined with CI treated cells. Bioinformatics analysis was carried out to determine its mechanism of action. Validation of proteomics results was done using Parallel Reaction Monitoring (PRM). Results: Cell culture experiments showed that LCL161 in combination with CI can significantly promote the apoptosis of breast cancer drug-resistant cells. Up-regulation of 92 proteins and down-regulation of 114 proteins protein were noted, of which 4 were selected for further validation. Conclusion: Our results show that LCL161 combined with CI can promote the apoptosis of drug-resistant breast cancer cells by down-regulation of RRM2, CDK4, and ITGB1 expression through Cancer pathways, p53 or PI3K-AKT signaling pathway. In addition, the expression of CDK4, RRM2, and CDC20 can be down-regulated by the nuclear receptor pathway to affect DNA transcription and replication, thereby promoting apoptosis of breast cancer drug-resistant cells.

Aims: Here, three liposomal formulations of DPPC/DPPG/Chol/DSPE-mPEG2000 (F1), DPPC/DPPG/Chol (F2) and HSPC/DPPG/Chol/DSPE-mPEG2000 (F3) encapsulating BTZ were prepared and characterized in terms of their size, surface charge, drug loading, and release profile. Mannitol was used as a trapping agent to entrap the BTZ inside the liposomal core. The cytotoxicity and anti-tumor activity of formulations were investigated in vitro and in vivo in mice bearing tumor. Background: Bortezomib (BTZ) is an FDA approved proteasome inhibitor for the treatment of mantle cell lymphoma and multiple myeloma. The low solubility of BTZ has been responsible for the several side effects and low therapeutic efficacy of the drug. Encapsulating BTZ in a nano drug delivery system; helps overcome such issues. Among NDDSs, liposomes are promising diagnostic and therapeutic delivery vehicles in cancer treatment. Objective: Evaluating anti-tumor activity of bortezomib liposomal formulations. Methods: Data prompted us to design and develop three different liposomal formulations of BTZ based on Tm parameter, which determines liposomal stiffness. DPPC (Tm 41°C) and HSPC (Tm 55°C) lipids were chosen as variables associated with liposome rigidity. In vitro cytotoxicity assay was then carried out for the three designed liposomal formulations on C26 and B16F0, which are the colon and melanoma cancer mouse-cell lines, respectively. NIH 3T3 mouse embryonic fibroblast cell line was also used as a normal cell line. The therapeutic efficacy of these formulations was further assessed in mice tumor models. Result: MBTZ were successfully encapsulated into all the three liposomal formulations with a high entrapment efficacy of 60, 64, and 84% for F1, F2, and F3, respectively. The findings showed that liposomes mean particle diameter ranged from 103.4 to 146.8nm. In vitro cytotoxicity studies showed that liposomal-BTZ formulations had higher IC50 value in comparison to free BTZ. F2-liposomes with DPPC, having lower Tm of 41°C, showed much higher anti-tumor efficacy in mice models of C26 and B16F0 tumors compared to F3-HSPC liposomes with a Tm of 55°C. F2 formulation also enhanced mice survival compared with untreated groups, either in BALB/c or in C57BL/6 mice. Conclusion: Our findings indicated that F2-DPPC-liposomal formulations prepared with Tm close to body temperature seem to be effective in reducing the side effects and increasing the therapeutic efficacy of BTZ and merits further investigation.

Background: Sonchus oleraceus is a large and widespread plant in the world. It is edible to humans as a leaf vegetable and is also used as a folklore medicinal herb in the treatment of infections and inflammatory disease, but limited research on its chemical constituents has been done. Objective: To isolate and identify the bioactive ingredients from S. oleraceus. Methods: 20kg of S. oleraceus was extracted twice with 75% alcohol. The concentrated extract was suspended in H2O and partitioned with petroleum ether, dichloromethane, ethyl acetate and n-butanol, respectively. The ethyl acetate phase was subjected to repeated normal chromatography on a silica gel column chromatography and eluted with a gradient of CH2Cl2-MeOH to give 12 crude fractions. Fraction 6 was subjected to ODS silica gel column chromatography, Sephadex LH-20 and HPLC to yield 1 and 2. Cell viability of 1 and 2 on A549, H292 and Caco2 cell lines were assayed by MTT method. Apoptosis analysis and apoptosis related proteins were detected subsequently. Results: Two new sesquiterpenes were isolated from S. oleraceus and identified by NMR spectra and HR-ESIMS. 1 selectively suppressed the viability of A549 and H292 cells with IC50 values of 14.2, and 19.5μM respectively, while possessing no cytotoxicity against Caco2 cells (IC50 > 100μM). 2 did not exhibit cytotoxicity against A549, H292 and Caco2 cells (IC50 > 100μM). 1 significantly decreased the density of live cells and could cause cell apoptosis at 10 and 20μM in a dose-dependent manner. After treatment of 1 for 24h, the level of cleaved caspase-3 was increased accompanied by the reduction in procaspase-3 expression, and the downregulation of Bcl-2 was associated with the enhancement of Bax expression. 1 could lead to the up-regulation of cytochrome c and activation of caspase-9. Conclusion: 1 and 2 are new sesquiterpenes from S. oleraceus. 1 could induce apoptosis in A549 and H292 cells through Bax/caspase-9 pathway.

Background: The authors investigated the NF-ΚB inhibitory role of three Benzisothiazolone (BIT) derivatives (1, 2 and 3) in Hodgkin’s Lymphoma cells (L428) which constitutively express activated NF-ΚB. All three compounds showed dose-dependent NF-ΚB inhibition (78.3, 70.7 and 34.6%) in the luciferase reporter gene assay and were found cytotoxic at IC50 values of 3.3μg/ml, 4.35μg/ml and 13.8μg/ml, respectively by the XTT assay. BIT 1and BIT 2 (but not BIT 3) suppressed both NF-ΚB subunits p50 and p65 in cytoplasmic and nuclear extracts in a concentration-dependent manner. Furthermore, BIT 1 showed a moderate synergistic effect with the standard chemotherapy drugs etoposide and doxorubicin, whereas BIT 2 and 3 showed a moderate additive effect to antagonistic effect. Cisplatin exhibited an antagonist effect on all the compounds tested under various concentrations, except in the case of 1.56μg/ml of BIT 3 with 0.156μg/ml of cisplatin. The compounds also inhibited the migration of adherent human lung adenocarcinoma cells (A549) in vitro. We conclude that especially BIT 1 and BIT 2 have in vitro anti-inflammatory and anti-cancer activities, which can be further investigated for future potential therapeutic use. Methods: Inspired by the electrophilic sulfur in Nuphar alkaloids, monomeric and dimeric benzisothiazolones were synthesized from dithiodibenzoic acid and their NF-ΚB inhibitory role was explored. NF-ΚB inhibition and cytotoxicity of the synthesized derivatives were studied using luciferase reporter gene assay and XTTassay. Immunocytochemistry studies were performed using L428 cells. Cell migration assay was conducted using the A549 cell line. L428 cells were used to conduct combination studies and the results were plotted using CompuSyn software. Results: Benzisothiazolone derivatives exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-ΚB inhibition. Potent compounds showed suppression of both NF-ΚB subunits p50 and p65 in a concentrationdependent manner, both in cytoplasmic and nuclear extracts. Combination studies suggest that benzisothiazolone derivatives possess a synergistic effect with etoposide and doxorubicin. Furthermore, the compounds also inhibited the migration of A549 cells. Conclusion: Benzisothiazolones bearing one or two electrophilic sulfur atoms as part of the heterocyclic framework exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-ΚB inhibition. In addition, these derivatives also exhibited a synergistic effect with etoposide and doxorubicin along with the ability to inhibit the migration of A549 cells. Our study suggests that BIT-based new chemical entities could lead to potential anticancer agents.

Background: The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. Objective: Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. Methods: The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. Results: Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. Conclusion: Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusion: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

Background: Identification of the antitumor role of tyrosine kinase inhibitors, such as TKI-258, may lead to novel therapeutics for Oral Squamous Cell Carcinoma (OSCC), which has high mortality rates. TKI-258 blocks Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), and Endothelial Growth Factor Receptor (VEGFRs). Objective: This study aimed to evaluate the effect of TKI-258 treatment on cell proliferation in SCC-4 cells of OSCC. Methods: BrdU and KI-67 assays were performed by using SCC-4 cells. Control was compared to 1, 5 and 10μM TKI-258 treatment. Control vehicle was compared to: 60μM LY294002 (LY), 2μM Wortmannin (WTN) and LY+WNT. Moreover, TKI 5μM treatment was compared to: TKI 5μM+LY; TKI 5 μM+WTN; TKI 5μM+LY+WTN. After 6h of treatments, immunofluorescence stained BrdU and KI-67 positive cells. Morphometry of proliferative cells was analyzed considering significance of p<0.05. Results: BrdU and KI-67 assays results were similar for all experiments. TKI-258 treatment leads to an important reduction in proliferation rate in SCC-4 cells in a concentration dependent manner. As expected, there was a significant reduction in the percentage of proliferative cells that had PI3K inhibited. When compared with TKI 5 treatment, proliferating cells were significantly lower with simultaneous PI3K inhibition. Conclusion: This study demonstrated that TKI-258 plays an anti-proliferative role on SCC-4 cells of OSCC. It could be interesting to block multiples pathways such as FGFRs, PDGFRs and VEGFRs. Therefore, TKI-258 is a promising option for novel therapeutics for OSCC, especially if associated with PI3K inhibition.