Cancer Cell Lines DU145 Research Articles

A novel normonoterpene glycoside and a new benzophenone derivative from Hypericum cerastioides and their in vitro cytotoxic activities

Phytochemical investigations on the aerial parts of Hypericum cerastioides led to the isolation and identification of a novel normonoterpene (1) and a previously undescribed benzophenone glycoside (3) along with eleven known secondary metabolites (2, 4–13). Their structures were deduced based on extensive 1D and 2D NMR analyses as well as HRESIMS. Compound 1 is a rare type of normonoterpene derivative with eight carbon atoms. The chemotaxonomic significance of the isolates was also discussed. Compounds were evaluated for their in vitro cytotoxic activities against SW480, A375, DU145 and MCF7 cancer cell lines using doxorubicin as a reference drug. Compounds 1 and 7 demonstrated weak cytotoxicity.

Synthesis, biological evaluation, and computational studies of thiazolyl hydrazone derivatives as triple mutant allosteric EGFR inhibitors

AbstractHerein, new thiazole‐2‐yl‐based hydrazone derivatives were synthesized and assessed for in vitro anticancer activity against wild type A549, MCF7, DU145, and mutant H1975 cancer cell lines by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Among all, 4‐(4‐Chlorophenyl)‐2‐(2‐((4‐methylthiazol‐5‐yl)methylene)hydrazineyl)thiazole (4b) elicited prominent anticancer activity against wild‐type epidermal growth factor receptor (WT‐EGFR) MCF7 cancer cell line with an IC50 value of 9.57 ± 1.80 μM, whereas 4‐Methyl‐5‐((2‐(4‐(4‐nitrophenyl)thiazol‐2‐yl)hydrazineylidene)methyl)thiazole (4c) showed appreciable activity with an IC50 value of 11 ± 0.7 μM against the mutated EGFR H1975 lung cancer cells. Doxorubicin and Osimertinib were used as the standard drugs for comparison of activity. Compound (4b) significantly increased early apoptosis (30.2%) and late apoptosis (7.6%) at a 5 μM concentration in comparison with the control (early apoptosis 2.5%, late apoptosis 1.2%). The molecular docking study was performed against mutant EGFR (T790M/C797S) (PDB: 5D41) enzyme to gain information about interactions of synthesized molecules with binding pockets. Moreover, ADME study and molecular dynamic simulation studies were accomplished to gain insight into drug‐likeness and conformational stability, respectively. The findings demonstrate a promising alignment between the observed anticancer effects and computational analyses.

Anticancer Activity of Sargassum fluitans Extracts in Different Cancer Cells.

The arrival of large quantities of Sargassum in the Mexican Caribbean Sea has generated major environmental, health and economic problems. Although Sargassum has been used in the generation of some commercial products, few studies have described its possible applications as a source of compounds with anticancer activity. This study aimed to evaluate the antiproliferative effects of different Sargassum extracts on various cancer cell lines. Furthermore, LC/QTOF-MS was used to identify the compounds related to the antiproliferative effect. First, determination of the seaweed was performed, and dichloromethane, chloroform and methanol extracts were obtained. The extracts were evaluated for their antiproliferative effects by MTT in breast (MDAMB- 231 and MCF-7), prostate (DU-145), lung (A549) and cervical (SiHa) cancer cell lines. Finally, LC/QTOFMS identified the compounds related to the antiproliferative effect. The authentication showed Sargassum fluitans as the predominant species. The extracts of dichloromethane and chloroform showed an antiproliferative effect. Interestingly, the fractionation of the chloroform extract showed two fractions (FC1 and FC2) with antiproliferative activity in MDA-MB-231, SiHa and A549 cancer cell lines. On the other hand, three fractions of dichloromethane extract (FD1, FD4 and FD5) also showed antiproliferative effects in the MDA-MB-231, MCF-7, SiHa and DU-145 cancer cell lines. Furthermore, LC/QTOF-MS revealed the presence of eight major compounds in FC2. Three compounds with evidence of anticancer activity were identified (D-linalool-3-glucoside, (3R,4S,6E,10Z)-3,4,7,11-tetramethyl-6,10-tridecadienal and alpha-tocotrienol). These findings showed that Sargassum fluitans extracts are a possible source of therapeutic agents against cancer and could act as scaffolds for new drug discovery.

Cytotoxicity Assay of Andrographolide Isolated from Sambiloto Herb [Andrographis paniculata (burm.f.)] against Lung Cancer A-549 and Prostate Cancer DU-145 Cell Lines

Cytotoxicity Assay of Andrographolide Isolated from Sambiloto Herb [Andrographis paniculata (burm.f.)] against Lung Cancer A-549 and Prostate Cancer DU-145 Cell Lines

Three new nonenes from culture broth of marine-derived fungus Albifimbria verrucaria and their cytotoxic and anti-viral activities.

Three new nonenes, verrucanonenes A‒C (1‒3), were isolated from culture broth of marine-derived fungus Albifimbria verrucaria. These compounds were isolated using silica gel column chromatography, reversed-phase medium pressure liquid chromatography, Sephadex LH-20 column chromatography, and preparative HPLC. Their structures were determined using a spectroscopic method. Cytotoxicities of these isolated compounds to A549, DU145, HCT116, and HT1080 cancer cell lines were assessed. Compounds 1‒3 exhibited cytotoxicities to DU145 cancer cell line, with IC50 values of 23.4, 28.6, and 20.1 µM, respectively. Compound 2 decreased H1N1-induced cytopathic effects on MDCK cells in a dose-dependent manner.

Three new phthalide derivatives from culture broth of Dentipellis fragilis and their cytotoxic activities.

Three new phthalide derivatives (1‒3) together with two known compounds, erinaceolactone B (4) and hericerin III (5), were isolated from the culture broth of Dentipellis fragilis. The chemical structures of 1‒5 were determined by analyses of their 1D-, 2D-NMR, and MS. The absolute configuration of 1 was determined by CD analysis. The isolated compounds were assessed for their cytotoxic activities against A549, DU145, HCT116, and HT1080 cancer cell lines. Compounds 1‒5 showed strong cytotoxic activities against DU145, with IC50 values ranging from 14.3 to 16.1 µM. Additionally, all compounds showed moderate or weak cytotoxic activities against all cell lines except for compounds 4 and 1 which showed no cytotoxic activities against A549 and HCT116 cancer cell lines, respectively. Against HT1080 cancer cell line, only compound 2 displayed moderate cytotoxic activity.

Aridanin and oleanane-3- O-β-D-glucoside-2′-acetamide obtained from Tetrapleura tetraptera (Schumach. & Thonn) Taub. (Fabaceae) induces potent apoptotic activity in human prostate cancer cells

Ethnopharmacological relevanceTetrapleura tetraptera (Schumach. and Thonn.) Taub. (Fabaceae) is a tropical plant that is used in Cameroon pharmacopeia for the treatment of many cancers including prostate cancer (PCa), which is a major cause of men's death worldwide. The objective of this study was to evaluate the anticancer properties as well as underlying mechanisms of isolates from T. tetraptera on DU145, PC3 and LNCaP cancer cell lines. Materials and methodsEight (8) compounds were purified from T. tetraptera stem bark extract through silica gel column chromatography (CC) and characterized using spectroscopic techniques (1D and 2D NMR), HRESIMS. Cell growth was assessed by a well-characterized MTT assay, while BrdU and clonogenicity assays provided information on the cell proliferation index. Further, the impact of the compounds on cell cycle progression and cell death were performed through Flow cytometry. Cell adhesion, cell migration and chemotaxis along with some proteins of epithelial-mesenchymal transition (EMT) were assayed. ResultsOut of the eight (1–8) isolates from T. tetraptera only oleanane-3-O-β-D-glucoside-2′-acetamide and aridanin showed potent cell growth arrest with an estimated CC50 of 15, 23, 16 and 17, 26, 16 μg/mL on DU145, PC3 and LNCaP cells, respectively. A 15% (DU145) and 25% (LNCaP) increase in apoptotic cells induced by oleanane-3-O-β-D-glucoside-2′-acetamide and aridanin at 10 μg/mL were noticed. Oleanane-3-O-β-D-glucoside-2′-acetamide and aridanin at 2.5 and 10 μg/mL reduced the number of cells in S-phase and raised cells in G2/M phase. At the same concentrations, they decreased the number of invading DU145 cells and increased the adherence of DU145 cells to fibronectin and collagen matrix at tested concentrations, accompanied by an increase in integrin β-1 (10 μg/mL) and integrin β-4 (2.5 μg/mL) expression. Furthermore, a down-regulation of pcdk1, cdk2, Bcl-2, N-Cad, vimentin and cytokeratine 8–18 was noticed while, p19, p27, p53 pAKT, Bax, caspase-3 and E-Cad were up-regulated. ConclusionsThis study outlines for the first time, the anticancer ability of compounds oleanane-3-O-β-D-glucoside-2′-acetamide (4) and aridanin (6) from Tetrapleura tetraptera and proposes their putative mechanisms of action.

Overexpression of SOX2 Gene by Histone Modifications: SOX2 Enhances Human Prostate and Breast Cancer Progression by Prevention of Apoptosis and Enhancing Cell Proliferation

Introduction: SOX2 plays a crucial role in tumor development, cancer stem cell maintenance, and cancer progression. Mechanisms of SOX2 gene regulation in human breast and prostate cancers are not established yet. Methods: SOX2 expression in prostate and breast cancer tissues and cell lines was determined by qRT-PCR, Western blot, and immunochemistry, followed by the investigation of pro-tumorigenic properties like cell proliferation, migration, and apoptosis by gene knockdown and treatment with epigenetic modulators and ChIP. Results: Prostate and breast cancer tissues showed very high expression of SOX2. All cancer cell lines DU145 and PC3 (prostate) and MCF7 and MDA-MB-231 (breast) exhibited high expression of SOX2. Inhibition of SOX2 drastically decreased cell proliferation and migration. Epigenetic modulators enhanced SOX2 gene expression in both cancer types. DNA methylation pattern in SOX2 promoter could not be appreciably counted for SOX2 overexpression. Activation of SOX2 gene promoter was due to very high deposition of H3K4me3 and H3K9acS10p and drastic decrease of H3K9me3 and H3K27me3. Conclusion: Histone modification is crucial for the overexpression of SOX2 during tumor development and cancer progression. These findings show the avenue of co-targeting SOX2 and its active epigenetic modifier enzymes to effectively treat aggressive prostate and breast cancers.

The cytotoxic and apoptotic effects of $\textit{Abies nordmanniana subsp. bornmülleriana Mattf }$ resin extract on prostate cancer cell cells

Cancer has become one of the most critical health issues, with an increasing incidence and mortality in recent years. Meanwhile, many studies are carried out on discovering new compounds which reflects effective results on cancer cells. Therefore, this study aimed to examine the cytotoxic, anti-proliferative and apoptotic effects on cancer cell lines by using the extract obtained from Uludağ Fir ($\textit{Abies nordmanniana subsp. bornmülleriana Mattf }$) resin. Uludağ Fir resin extract was obtained by applying the methanol extraction method. In our study, fibroblast cell L-929, human metastatic prostate cancer PC-3 and human metastatic prostate cancer DU-145 cell lines were cultured in RPMI-1640 medium. The effects of the resin extract concentrations on the viability of the cells were determined with the Muse™ Cell Count & Viability test. In addition, apoptosis and cell cycle phases of the cells were determined using the Muse™ cell analyzer. Finally, RT-qPCR analysis was performed to determine the resin extract effect on pro-apoptotic and anti-apoptotic gene expression. The apoptotic effect of Uludağ Fir resin extract on cancer cell lines was significantly higher in contrast to the healthy normal cells. In addition, it was determined that Uludağ Fir extract caused G0/G1 cell cycle arrest in cancer cells. In RT-qPCR analysis, the pro-apoptotic gene expression levels were apparently increased in cancer cells, which was followed by a decrease in the anti-apoptotic gene expression levels. All taken together, these results indicate that Uludağ Fir resin extract exerts two prong effects as it induces a cell cycle arrest and apoptotic pathway activation on human prostate cancer cell lines.

Molecular and metabolic alterations of 2,3-dihydroquinazolin-4(1H)-one derivatives in prostate cancer cell lines

Prostate cancer (PC) is the second most common tumor in males worldwide. The lack of effective medication and the development of multidrug resistance towards current chemotherapeutic agents urge the need to discover novel compounds and therapeutic targets for PC. Herein, seven synthesized 2,3-dihydroquinazolin-4(1H)-one analogues were evaluated for their anticancer activity against PC3 and DU145 cancer cell lines using MTT, scratch-wound healing, adhesion and invasion assays. Besides, a liquid chromatography mass spectrometry (LC–MS)-based metabolomics approach was followed to identify the biochemical pathways altered in DU145 cancer cells upon exposure to dihydroquinazolin derivatives. The seven compounds showed sufficient cytotoxicity and significantly suppressed DU145 and PC3 migration after 48 and 72 h. C2 and C5 had the most potent effect with IC50 < 15 µM and significantly inhibited PC cell adhesion and invasion. Metabolomics revealed that C5 disturbed the level of metabolites involved in essential processes for cancer cell proliferation, progression and growth including energy production, redox homeostasis, amino acids and polyamine metabolisms and choline phospholipid metabolism. The data presented herein highlighted the importance of these compounds as potential anticancer agents particularly C5, and pointed to the promising role of metabolomics as a new analytical approach to investigate the antiproliferative activity of synthesized compounds and identify new therapeutic targets.

Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (2) exhibiting the lowest GI50 of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1-4; however, this was not always translated to the observed cytotoxicity.

A peptide derived from adaptor protein STAP-2 inhibits tumor progression by downregulating epidermal growth factor receptor signaling

Signal-transducing adaptor family member-2 (STAP-2) is an adaptor protein that regulates various intracellular signals. We previously demonstrated that STAP-2 binds to epidermal growth factor receptor (EGFR) and facilitates its stability and activation of EGFR signaling in prostate cancer cells. Inhibition of this interaction may be a promising direction for cancer treatment. Here, we found that 2D5 peptide, a STAP-2-derived peptide, blocked STAP-2-EGFR interactions and suppressed EGFR-mediated proliferation in several cancer cell lines. 2D5 peptide inhibited tumor growth of human prostate cancer cell line DU145 and human lung cancer cell line A549 in murine xenograft models. Additionally, we determined that EGFR signaling and its stability were decreased by 2D5 peptide treatment during EGF stimulation. In conclusion, our study shows that 2D5 peptide is a novel anticancer peptide that inhibits STAP-2-mediated activation of EGFR signaling and suppresses prostate and lung cancer progression.

Synthesis, biological evaluation and in-silico ADME studies of novel series of thiazolidin-2,4-dione derivatives as antimicrobial, antioxidant and anticancer agents

BackgroundA novel series of thiazolidine-2,4-dione molecules was derived and their chemical structures were established using physiochemical parameters and spectral techniques (1H-NMR, IR, MS etc.). The synthesized molecule were then evaluated for their antioxidant, anticancer and antimicrobial potential.Results and discussionSerial tube dilution method was employed to evaluate the antimicrobial potential against selected fungal and bacterial strains by taking fluconazole and cefadroxil as reference antifungal and antibacterial drugs respectively. 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity was used to assess the antioxidant potential of the synthesized analogues. Further, the anticancer potential of the selected molecules was assessed against DU-145 cancer cell lines using MTT assay. The drug-likeness was also evaluated by studying in-silico ADME parameters of the synthesized analogues.ConclusionIn antioxidant evaluation studies, the analogue H5 with IC50 = 14.85 μg/mL was found to be the most active molecule. The antimicrobial evaluation outcomes suggested that the molecules H5, H13, H15 and H18 possessed moderate to promising activity against the selected species of microbial strains having MIC range 7.3 µM to 26.3 µM. The results of anticancer evaluation revealed that all the screened derivatives possess mild anticancer potential. The in-silico ADME studies revealed that all the compounds were found to be drug-like.

Bioassay-Guided extraction of andrographis paniculata for intervention of in-vitro prostate cancer progression in metabolic syndrome environment.

Metabolic syndrome (MetS) is a risk factor for prostate cancer (PCa) progression. Thus, this life-threatening disease demands a proactive treatment strategy. Andrographis paniculata (AP) is a promising candidate with various medicinal properties. However, the bioactivity of AP is influenced by its processing conditions especially the extraction solvent. In the present study, bioassay-guided screening technique was employed to identify the best AP extract in the management of MetS, PCa, and MetS-PCa co-disease in vitro. Five AP extracts by different solvent systems; APE1 (aqueous), APE2 (absolute methanol), APE3 (absolute ethanol), APE4 (40% methanol), and APE5 (60% ethanol) were screened through their phytochemical profile, in-vitro anti-cancer, anti-obese, and anti-hyperglycemic properties. The best extract was further tested for its potential in MetS-induced PCa progression. APE2 contained the highest andrographolide (1.34 ± 0.05mg/mL) and total phenolic content (8.85 ± 0.63 GAE/gDW). However, APE3 has the highest flavonoid content (11.52 ± 0.80 RE/gDW). APE2 was also a good scavenger of DPPH radicals (EC50 = 397.0µg/mL). In cell-based assays, among all extracts, APE2 exhibited the highest antiproliferative activity (IC50 = 57.5 ± 11.8µg/mL) on DU145 cancer cell line as well as on its migration activity. In in-vitro anti-obese study, all extracts significantly reduced lipid formation in 3T3-L1 cells. The highest insulin-sensitizing and -mimicking actions were exerted by both APE2 and APE3. Taken together, APE2 showed collectively good activity in the inhibition of PCa progression and MetS manifestation in vitro, compared to other extracts. Therefore, APE2 was further investigated for its potential to intervene DU145 progression induced with leptin (10-100ng/mL) and adipocyte conditioned media (CM) (10% v/v). Interestingly, APE2 significantly diminished the progression of the cancer cell that has been pre-treated with leptin and CM through cell cycle arrest at S phase and induction of cell death. In conclusion, AP extracts rich with andrographolide has the potential to be used as an alternative to ameliorate PCa progression induced by factors highly expressed in MetS.

Assessment the Effect of Human Umbilical Cord Wharton's Jelly Stem Cells on the Expression of Homing Genes: CXCR4 and VLA-4 in Cell Line of Prostate Cancer.

Background : Prostate cancer is the second most common cancer in the male that affects the health, social and economic life of person. Different compounds such as Wharton's jelly, have been used to treat prostate cancer. Wharton's jelly is a tissue rich in cells with mesenchymal morphology. Wharton's jelly compound inhibited the growth of various cancer cells, including ovarian, osteosarcoma, breast, and prostate cancers, and also reduced the expression of CXCR4 and VLA-4 genes involved in the metastasis process. Materials and Methods: To do this research, Wharton's jelly stem cells and DU145 cancer cell line were cultured. After cell culture, the effect of Wharton's jelly on this cell line was evaluated by scratching and MTT assay. The expression of CXCR4 and VLA-4 genes was also evaluated by Real-time PCR. Results: The results of MTT and Scratching tests showed that Wharton's jelly inhibited the growth of DU145 cancer cells and also decreased the expression level of CXCR4 and VLA-4 genes. Conclusion: The results of this study showed that Wharton's jelly can be considered as an effective compound for decreasing metastasis of prostate cancer.

Indole alkaloid ellipticine as efficient multitarget compound

First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions

Synthesis and biological evaluation of aryl derivatives of isoxazole pyrazolo[1,5-a] pyrimidines as anticancer agents

ABSTRACT: A new library of different substituted aryl derivatives of isoxazole-pyrazolo[1,5-a]pyrimidine (10a–j) were prepared, confirmed their structures by 1HNMR, 13CNMR and mass spectral data. Furthermore, the preliminary anticancer activities of newly developed compounds (10a–j) were tested against four human cancer cell lines PC3 (prostate), DU-145 (Prostate), A549 (lung) and MCF-7 (breast) by utilizing of MTT method. The obtained results of were compared with standard reference etoposide. Among all, compounds (10a, 10b, 10c, 10e, 10i and 10j) displayed highest anticancer activities than standard. Predominantly, one compound 10a with 3,4,5-trimethoxy substituent on the aryl ring showed excellent activity. The molecular modeling studies indicated the interactions of synthesized compounds with SARM, and DNA via hydrogen bonds and hydrophobic interactions.

Terpenoids from the Stem bark of Aglaia elaeagnoidea and their cytotoxic activity against HeLa and DU145 Cancer Cell lines

Aglaia is the largest genus of the Meliaceae family which contains terpenoid compounds. This type of compounds showed a diverse structures and biological activities that can be found in natural resources. Aglaia elaeagnoidea is a species from Aglaia genus that only has a few previous research. This study was aimed to isolate and determine the chemical structure of terpenoid compounds from the ethyl acetate extract of A. elaeagnoidea stem bark. Ethyl acetate extracts were separated and purified by various chromatographic techniques to obtain compounds 1-5. Compounds 1-5 were identified their chemical structures by spectroscopic methods (IR, MS, and NMR) and comparison with previous reported spectral data. Compounds 1 and 2 were identified as eudesmane-type sesquiterpenoids, 5-epi-eudesm-4(15)-ene-1β,6β-diol (1) and 6α-Hydroxy-eudesm-4(15)-en-1-one (2). Compounds 3-5 were identified as dammarane-type triterpenoids, 20S,24S-epoxy-25-hydroxydammarane-3-one (3), 20S,24S-epoxydammarane-3α,25-diol (4), and 3α-epi-cabraleahydroxy lactone (5). These compounds are first time reported from this plant. Compounds 1-5 were tested for cytotoxicity against HeLa cervical cancer cell and DU145 prostate cancer cell and as a result, compound 4 (20S,24S-epoxydammarane-3α,25-diol) showed the stronger activity compared to other compounds.

BK002 Induces miR-192-5p-Mediated Apoptosis in Castration-Resistant Prostate Cancer Cells via Modulation of PI3K/CHOP.

BK002 consists of Achyranthes japonica Nakai (AJN) and Melandrium firmum Rohrbach (MFR) that have been used as herbal medicines in China and Korea. AJN and MFR have been reported to have anti-inflammatory, anti-oxidative, and anti-cancer activities, although the synergistic targeting multiple anti-cancer mechanism in castration-resistant prostate cancer (CRPC) has not been well reported. However, the drug resistance and transition to the androgen-independent state of prostate cancer contributing to CRPC is not well studied. Here, we reported that BK002 exerted cytotoxicity and apoptosis in CRPC PC3 cell lines and prostate cancer DU145 cell lines examined by cytotoxicity, western blot, a LIVE/DEAD cell imaging assay, reactive oxygen species (ROS) detection, quantitative real-time polymerase chain reaction (RT-PCR), and transfection assays. The results from our investigation found that BK002 showed more cellular cytotoxicity than AJN and MFR alone, suggesting that BK002 exhibited potential cytotoxic properties. Consistently, BK002 increased DNA damage, and activated p-γH2A.X and depletion of survivin-activated ubiquitination of pro-PARP, caspase9, and caspase3. Notably, live cell imaging using confocal microscopy found that BK002 effectively increased DNA-binding red fluorescent intensity in PC3 and DU145 cells. Also, BK002 increased the anti-proliferative effect with activation of the C/EBP homologous protein (CHOP) and significantly attenuated PI3K/AKT expression. Notably, BK002-treated cells increased ROS generation and co-treatment of N-Acetyl-L-cysteine (NAC), an ROS inhibitor, significantly preventing ROS production and cellular cytotoxicity, suggesting that ROS production is essential for initiating apoptosis in PC3 and DU145 cells. In addition, we found that BK002 significantly enhanced miR-192-5p expression, and co-treatment with BK002 and miR-192-5p inhibitor significantly reduced miR-192-5p expression and cellular viability in PC3 and DU145 cells, indicating modulation of miR-192-5p mediated apoptosis. Finally, we found that BK002-mediated CHOP upregulation and PI3K downregulation were significantly reduced and restrained by miR-192-5p inhibitor respectively, suggesting that the anti-cancer effect of BK002 is associated with the miR-192-5p/PI3K/CHOP pathway. Therefore, our study reveals that a combination of AJN and MFR might be more effective than single treatment against apoptotic activities of both CRPC cells and prostate cancer cells.

Synthesis of curcumin based imidazo[2,1-b]thiazole derivatives and their biological evaluation as antiproliferative agents

Motivated by the antiproliferative potential of curcumin and imidazothiazoles, a series of curcumin based imidazo[2,1- b ] thiazole derivatives have been prepared, characterized and evaluated for their anticancer activity against various human cancer cell lines. These synthesized compounds have been found to have appreciable to moderate activity. Consequently, compounds 8a and 8g display noteworthy cytotoxicity with IC 50 values of 7.2 μM and 4.7 μM, respectively, against A549 cell line. Furthermore, compounds 8a , 8b and 8g exhibit substantial cytotoxicity with IC 50 values ranging between 9.1 μM to 9.9 μM respectively, against HeLa cell line. Interestingly, compounds 8a and 8g exhibit appreciable cytotoxicity with IC 50 values ranging between 7.5 μM to 8.7 μM respectively, against DU145 cancer cell line. Overall, four compunds ( 8a, 8b, 8g and 8h ) demonstrate IC 50 values less than 10 μM against selected human cancer cell lines. They could be taken further for investigation of their mode of action and other parameters.