A role for RIO kinases in the crosshair of cancer research and therapy.

RIO (right open reading frame) family of kinases including RIOK1, RIOK2 and RIOK3 are known for their role in the ribosomal biogenesis. Dysfunction of RIO kinases have been implicated in malignancies, including acute myeloid leukemia, glioma, breast, colorectal, lung and prostatic adenocarcinoma suggesting RIO kinases as potential targets in cancer. In vitro, in vivo and clinical studies have demonstrated that RIO kinases are overexpressed in various types of cancers suggesting important roles in tumorigenesis, especially in metastasis. In the context of malignancies, RIO kinases are involved in cancer-promoting pathways including AKT/mTOR, RAS, p53 and NF-κB and cell cycle regulation. Here we review the role of RIO kinases in cancer development emphasizing their potential as therapeutic target and encouraging further development and investigation of inhibitors in the context of cancer.

Quercetin ameliorates Di (2-ethylhexyl) phthalate-induced nephrotoxicity by inhibiting NF-κB signaling pathway.

This study aimed to evaluate the possible protective effects of quercetin, a natural flavonoid, against nephrotoxicity induced by Di (2-ethylhexyl) phthalate (DEHP) in kidney tissue of rats and human embryonic kidney (HEK) 293 cell line. The HEK-293 cells were treated with different concentrations of quercetin 24 h before treatment with monoethylhexyl phthalate (MEHP). Male rats were treated with 200-mg/kg DEHP, 200-mg/kg DEHP plus quercetin (50 and 100 mg/kg), and 200-mg/kg DEHP plus vitamin E (20 mg/kg) for 45 days by gavage. Quercetin treatment reduced cytotoxicity and oxidative damage inducing by MEHP in HEK-293 cells. The in vivo findings showed that 100-mg/kg quercetin significantly suppressed DEHP-induced kidney damage. For exploring the involved mechanisms, the expressions of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) genes were determined via real-time Polymerase chain reaction (PCR) assay. High dose of quercetin significantly decreased the gene expressions of NF-κB and TNFα, whereas the alternations of Nrf2 and HO-1 gene expressions were not significant in quercetin groups in compared with DEHP group. These findings suggested that the suppression of DEHP-induced nephrotoxicity via quercetin is correlated, at least in part, with its potential to regulate NF-κB signaling pathway.

Comparative proteomics study of proteins involved in induction of higher rates of cell death in mitoxantrone-resistant breast cancer cells MCF-7/MX exposed to TNF-α.

OBJECTIVES: Resistance to medications is one of the main complications in chemotherapy of cancer. It has been shown that some multidrug resistant cancer cells indicate more sensitivity against cytotoxic effects of TNF-α compared to their parental cells. Our previous findings indicated vulnerability of the mitoxantrone-resistant breast cancer cells MCF-7/MX to cell death induced by TNF-α compared to the parent cells MCF-7. In this study, we performed a comparative proteomics analysis for identification of proteins involved in induction of higher susceptibility of MCF-7/MX cells to cytotoxic effect of TNF-α. MATERIALS AND METHODS: Intensity of protein spots in 2D gel electrophoresis profiles of MCF-7 and MCF-7/MX cells were compared with Image Master Platinum 6.0 software. Selected differential protein-spots were identified with MALDI-TOF/TOF mass spectrometry and database searching. Pathway analyses of identified proteins were performed using PANTHER, KEGG PATHWAY, Gene MANIA and STRING databases. Western blot was performed for confirmation of the proteomics results. RESULTS: Our results indicated that 48 hr exposure to TNF-α induced 87% death in MCF-7/MX cells compared to 19% death in MCF-7 cells. Forty landmarks per 2D gel electrophoresis were matched by Image Master Software. Six proteins were identified with mass spectrometry. Western blot showed that 14-3-3γ and p53 proteins were expressed higher in MCF-7/MX cells treated with TNF-α compared to MCF-7 cells treated with TNF-α. CONCLUSION: Our results showed that 14-3-3 γ, prohibitin, peroxiredoxin 2 and P53 proteins which were expressed differentially in MCF-7/MX cells treated with TNF-α may involve in the induction of higher rates of cell death in these cells compared to TNF-α-treated MCF-7 cells.

Wnt-ß-catenin Signaling Pathway, the Achilles' Heels of Cancer Multidrug Resistance.

BACKGROUND: Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR. METHODS: In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, ß-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. RESULT AND CONCLUSION: Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/ß- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/ß-catenin signaling can be a potential target for modulating cancer MDR.

Colchicine-like ß-acetamidoketones as inhibitors of microtubule polymerization: Design, synthesis and biological evaluation of in vitro anticancer activity.

OBJECTIVES: In this study a series of novel colchicine-like ß-acetamidoketones was designed and synthesized as potential tubulin inhibitors. MATERIALS AND METHODS: The cytotoxicity of the novel synthesized ß-acetamidoketones was assessed against two cancerous cell lines including MCF-7 (human breast cancer cells) and A549 (adenocarcinomic human alveolar basal epithelial cells) employing the MTT test. Tubulin polymerization test was done by using a commercial kit (tubulin polymerization assay kit). RESULTS: In general, the cytotoxicity activities were highly dependent on the aromatic substitution pattern of phenyl ring at ß position of ß-acetamidoketones. Based upon, compound 4f possessing the same structural elements of colchicine and chalcone 1, revealed the most cytotoxicity more than the other ß-acetamidoketone against the cancerous cell lines and showed moderate antitubulin effect. The tubulin inhibitory effect of 4f, colchicine and chalcone 1 were consistent with their antiproliferative activities. Molecular docking studies of 4f, into the colchicine-binding site of tubulin exhibited possible mode of interaction between this compound and tubulin. CONCLUSION: The structure activity relationship (SAR) data attained showed that the presence of trimethoxy phenyl attached to carbonyl group of ß-acetamidoketones and a methoxy group at para position of the other ring are essential for cytotoxic activity. In general, the cytotoxicity activities were highly dependent on the aromatic substitution pattern of phenyl ring at ß position of ß-acetamidoketones.

In vitro evaluation of dihydropyridine-3-carbonitriles as potential cytotoxic agents through PIM-1 protein kinase inhibition.

PIM-1 protein kinase inhibitor belongs to a novel class of serine/threonine kinases. As PIM-1 is overexpressed in cancer cells and possesses oncogenic functions, its inhibition provides a new option in cancer therapy. In this study, in vitro inhibitory effects of seven analogues of 1, 2-dihydropyridine-3-carbonitrile derivatives Ia-c, IIa-d on the activity of recombinant PIM-1 were evaluated using dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The PIM-1 protein kinase inhibitory potencies and the cytotoxicity effects of tested compounds were respectively as follows: Ic > IIa > Ia > IIb > Ib > IId > IIc and IIb > IIa > Ia > IIc > Ic > Ib > IId, respectively. The compound Ic with methylthio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-imino-1, 2-dihydropyridine-3- carbonitrile structure showed the strongest PIM-1 inhibitory effect (IC50 = 111.01 nM), while the compound IIc with methythio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-oxo-1, 2-dihydropyridine-3- carbonitrile structure exhibited the least inhibition activity (IC50 = 433.71 nM). The docking results showed that all tested compounds localized appropriately in the middle of binding cavity after docking procedure, demonstrating suitable interactions between ligands and protein. This study demonstrated that the PIM-1 inhibitory potencies of newly synthesized compounds were in submicromolar concentrations (IC50 < 150 nM) while they exhibited low cytotoxicity on HT-29 cell line (IC50> 130 µM). Altogether, our data indicated that compounds Ic, IIa, Ia could be considered as new potent non-toxic PIM-1 inhibitors which could be used in combination with routine anti-proliferative drugs.

TNF-α exerts cytotoxic effects on multidrug resistant breast cancer MCF-7/MX cells via a non-apoptotic death pathway.

Tumor necrosis factor-α (TNF-α) is a cytokine involved in the various physiopathological processes such as autoimmune disorders and inflammation related diseases. Some multidrug resistant (MDR) cancer cell lines including MCF-7/MX are more vulnerable to cytotoxic effects of TNF-α than their parental lines. In this study, breast cancer cell line MCF-7 and its MDR derivative MCF-7/MX were exposed to TNF-α afterward various downstream signaling mediators of TNF-α were analyzed. Although, treatment of MCF-7 cells with TNF-α activated NF-kB and caused RIP1 ubiquitination, TNF-α exposure led to JNK and RIP1 phosphorylation in MCF-7/MX cells. In both cell lines TNF-α did not activate the caspase cascade. Moreover, AnexinV/PI analysis showed that cytotoxic effects of TNF-α on MCF-7/MX is mediated via apoptosis independent mechanisms and inhibition of RIP1 kinase activity using necrostatin-1 revealed that kinase activity of RIP1 plays role in the production of ROS, activation of JNK and cellular death following exposure of MCF-7/MX cells to TNF-α. Overall, it seems that RIP1 ubiquitination and NF-kB activation are prosurvival signaling mediators protecting MCF-7 cells against cytotoxic effects of TNF-α while TNF-α drives MCF-7/MX cells to non-apoptotic cellular death via kinase activity of RIP1, activation of JNK and ROS production.

Curcumin: An Effective Inhibitor of Interleukin-6.

Curcumin is apolyphenolic compound found in the dietary spice turmeric. Anti-inflammatory effects of turmeric have been known for centuries and extensive studies over the last two to three decades revealed that curcumin is a key component in the anti-inflammatory effects of turmeric. Chronic inflammation is involved in the various pathologic states and curcumin demonstrated therapeutic effects in different inflammation-related diseases in various in vivo, in vitro and human based studies through regulation of different signaling molecules including transcription factors, chemokines, cytokines, tumor suppressor genes, adhesion molecules and microRNAs. Interleukin-6 (IL-6) plays important roles in various events during inflammation including regulation of antibody (and autoantibody) production, activation of T cells, differentiation of B cells, increased production of acute-phase proteins, hematopoiesis and angiogenesis, vascular permeability, and osteoclast differentiation. IL-6 is also involved in pathogenesis of different inflammatory diseases. There are numerous studies demonstrating association of down-regulation of IL-6 and/or inhibition of IL-6 signaling with therapeutic effects of curcumin suggesting a role for modulation of IL-6 in anti-inflammatory effects of curcumin. Moreover, curcumin can be considered as potential therapy against IL-6 involved pathologic stats. In this narrative review, the in vitro, experimental and clinical studies that report association of IL-6 inhibition and therapeutic effects of curcumin are discussed.

Synthesis and biological evaluation of quinoline analogues of flavones as potential anticancer agents and tubulin polymerization inhibitors.

A new series of 2-aryl-trimethoxyquinoline analogues was designed and synthesized as tubulin inhibitors using methoxylated flavones as the lead compounds. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, MCF-7/MX, A-2780, and A-2780/RCIS. All the alcoholic derivatives (6a-6e) showed significant cytotoxic activity with IC50 in the range of 7.98-60 µM. The flow cytometry analysis of the four human cancer cell lines treated with 6e and 5b showed that 6e induced cell cycle arrest at G2/M phase and apoptosis as well. The effect of quinolines on tubulin polymerization was also evaluated. Compound 6e that demonstrated the best antiproliferative activity in the series was identified as the most potent inhibitor of tubulin polymerization as well. Molecular docking studies of 6e into the colchicine-binding site of tubulin displayed possible mode of interaction between this compound and tubulin.

Reactive Oxygen Species Mediate TNF-x237A; Cytotoxic Effects in the Multidrug-Resistant Breast Cancer Cell Line MCF-7/MX.

BACKGROUND: Reactive oxygen species (ROS) are not only harmful by-products of the cellular metabolism but also essential components of cell signaling, contributing to various physiologic features including cytokine and growth factor signaling. Here, we examined the role of ROS in the cytotoxic effects of tumor necrosis factor-x237A; (TNF-x237A;) in MCF-7 cells and their drug-resistant counterparts, MCF-7/MX cells. MATERIALS AND METHODS: ROS levels were evaluated following TNF-x237A; exposure using 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA) as fluorescent probe, and the TNF-x237A; cytotoxic effects were examined using the dimethylthiazolyl-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: TNF-x237A; led to ROS accumulation only in MCF-7/MX and not in MCF-7 cells. The role of ROS in the cytotoxic effects of TNF-x237A; was further evaluated by inhibition of ROS accumulation in MCF-7/MX cells and by induction of ROS generation in MCF-7 cells along with TNF-x237A; treatment. ROS accumulation sensitized the MCF-7 cells to the cytotoxic effects of TNF-x237A; while inhibition of ROS accumulation attenuated the cytotoxic effects of TNF-x237A; in MCF-7/MX cells. Following TNF-x237A; treatment, the activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase) were evaluated in both cell lines. The results of the enzyme assays revealed that superoxide dismutase activity was enhanced in MCF-7 but not in MCF-7/MX cells. CONCLUSIONS: ROS accumulation in MCF-7/MX cells may be involved in the higher cytotoxic effects of TNF-x237A; in the MCF-7/MX cell line.

Inhibition of Akt phosphorylation attenuates resistance to TNF-α cytotoxic effects in MCF-7 cells, but not in their doxorubicin resistant derivatives.

OBJECTIVES: Acquisition of TNF-α resistance plays role in the onset and growth of malignant tumors. Previous studies have demonstrated that MCF-7 cell line and its doxorubicin resistant variant MCF-7/Adr are resistant against the cytotoxic effects of TNF-α. In this study, we investigated the role of Akt activation in resistance of MCF-7 and MCF-7/Adr against TNF-α cytotoxicity. MATERIALS AND METHODS: The role of Akt activation in TNF-α cytotoxicity was investigated by MTT cell viability assay following treatment of the cells with the chemical inhibitor of Akt activation with or without TNF-α treatment. Phosphorylation of Akt at Ser473 before and after 72 hr TNF-α treatment was also determined by western blot. RESULTS: TNF-α treatment led to enhancement of Akt Ser473 phosphorylation. Treatment of MCF-7 cells with TNF-α along with Akt-inhibitor agent, tricribine, attenuated Akt Ser473 phosphorylation and sensitized these cells to the cytotoxic effects of TNF-α in a dose and time dependent manner while tricribine treatment did not cause any significant cytotoxicity in MCF-7/Adr cells alone or in combination with TNF-α. CONCLUSION: These results demonstrate that Akt phosphorylation plays pivotal role in the resistance of MCF-7 cells against TNF-α-induced cytotoxicity while it might play no significant role in the resistance of MCF-7/Adr cells against TNF-α.

Highly Oxygenated Sesquiterpene Lactones from Cousinia aitchisonii and their Cytotoxic Properties: Rhaserolide Induces Apoptosis in Human T Lymphocyte (Jurkat) Cells via the Activation of c-Jun n-terminal Kinase Phosphorylation.

Infrared-guided chromatographic fractionation of sesquiterpene lactones from the extracts of Cousinia aitchisonii and Cousinia concolor led to the isolation of five pure compounds. A new sesquiterpene lactone, namely, aitchisonolide, and two known sesquiterpene lactones (desoxyjanerin and rhaserolide) were isolated from C. aitchisonii and two known lignans (arctiin and arctigenin) from C. concolor. The structures of these compounds were elucidated by one-dimensional and two-dimensional nuclear magnetic resonance techniques, as well as high-resolution mass spectrometry. The purified and characterized compounds were subjected to cytotoxicity assay. The sesquiterpene lactones desoxyjanerin and rhaserolide showed significant cytotoxic activities against five different cancer cell lines and the normal human embryonic kidney cell line. Rhaserolide was chosen to evaluate the possible mechanism of action. Western blot analysis revealed that rhaserolide could induce apoptosis in Jurkat cells via the activation of c-Jun n-terminal kinase phosphorylation.

MicroRNA-34a and its target genes: Key factors in cancer multidrug resistance.

Following the first small non-coding RNA identification in 1993, accumulated knowledge on the biogenesis, homeostasis and functional roles of microRNAs in different physiological and pathophysiological conditions has been discovered. MicroRNAs act through epigenetic regulation of gene expression. MiR-34a is a member of the MiR-34 family that is involved in p53 pathways, and is implicated in cell death/survival signaling. MiR-34a is associated with G1 cell cycle arrest, senescence and apoptosis, thereby possessing a tumor suppressor activity. Deregulation of MiR-34a has been reported in several types of cancers. MiR-34a downregulation has been correlated with cancer multidrug resistance (MDR), which is a major challenge for successful cancer chemotherapy. MiR-34a mimetic agents have been shown to attenuate drug resistance in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings dealing with the role of miR-34a downregulation in MDR, and potential therapeutic opportunities arising from this role of miR-34a.

Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance.

Multidrug resistance (MDR) is a phenomenon through which tumor cells develop resistance against the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. The most consistent feature in MDR is overexpression and/or overactivity of ATP-dependent drug efflux transporters. Other mechanisms such as overexpression of drug-detoxifying enzymes and alterations in pro-survival or pro-death signaling pathways are also responsible for MDR. Inflammatory mediators including interleukin-6 (IL-6) play important roles in various events during inflammation and are also involved in development and progression of several types of cancers. Mounting evidence has suggested a crosstalk between IL-6 and MDR in cancer, highlighting the role of IL-6 in chemotherapy response, and the potential opportunity to control MDR through modulation of IL-6 expression. Upregulation of IL-6 has been shown to promote MDR through activation of Janus kinases (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), and Ras-MAPK (mitogen-activated protein kinase) pathways. Activation of the aforementioned pathways changes the expression pattern of several genes involved in proliferation, survival and cell cycle regulation, thus facilitating MDR. Conversely, IL-6 inhibition using different strategies (antibodies, siRNA, and antisense transfection) has been shown to improve tumor responsiveness and mitigate MDR in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings on the role of IL-6 in MDR, and potential therapeutic opportunities arising from this role of IL-6.

Image-Based Analysis to Predict the Activity of Tariquidar Analogs as P-Glycoprotein Inhibitors: The Importance of External Validation.

Permeability glycoprotein (P-gp) is involved in the pathology of various diseases including cancer and epilepsy, mainly through the translocation of some medicines across the cell membrane. Here, we employed image-based quantitative structure-activity relationship (QSAR) models to predict the P-gp inhibitory activity of some Tariquidar derivatives. The structures of 65 Tariquidar derivatives and their P-gp inhibition activities were collected from the literature. For each compound, the pixels of bidimensional images and their principal components (PCs) were calculated using MATLAB software. Various statistical methods including principal component regression, artificial neural networks, and support vector machines were employed to investigate the correlation between the PCs and the activity of the compounds. The predictability of the models was investigated using external validation and applicability domain analysis. An artificial neural network-based model demonstrated the best prediction results for the test set. Moreover, external validation analysis of the developed models supports the idea that R(2) cannot assure the validity of QSAR models and another criterion, i.e., the concordance correlation coefficient (CCC) parameter, should be involved to evaluate the validity of the QSAR models. The results of this study indicate that image analysis could be as suitable as descriptors calculated by commercial software to predict the activity of drug-like molecules.

TNF-α exerts higher cytotoxic effect on MCF-7 multidrug resistant derivative, role of Akt activation.

BACKGROUND: TNF-α is a pleiotropic cytokine which activates different downstream signaling pathways leading cells to death or survival. In some in vitro examinations, TNF-α treatment demonstrated higher cytotoxic effects on MDR cancer cell lines compared to their parental counterparts. OBJECTIVE: This study investigated effects of TNF-α in MCF-7 and its mitoxantrone (MX) resistant variant of breast cancer cell line, MCF-7/MX. Moreover, the role of Akt phosphorylation in TNF-α effect was also investigated. METHODS: Akt phosphorylation was evaluated using Western blotting and TNF-α effect was examined using cytotoxicity assay following treatment of the cells with TNF-α . RESULTS: TNF-α treatment exerted higher cytotoxic effects on MCF-7/MX compared to MCF-7 cells. Akt phosphorylation was enhanced following TNF-α treatment in MCF-7 cells while it did not change in MCF-7/MX cells. TNF-α treatment along with inhibition of Akt phosphorylation by a chemical inhibitor triciribine, sensitized MCF-7 cells to cytotoxic effects of TNF-α. Moreover, activation of PI3K/Akt pathway by activator peptide 740 Y-P in MCF-7/MX cells enhanced resistance against TNF-α cytotoxicity. CONCLUSION: Alteration in Akt phosphorylation is involved in the resistance of MCF-7 cells and sensitivity of MCF-7/MX cells to TNF-α -induced cytotoxicity, respectively.

Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins.

In the present study, fifteen sesquiterpene coumarins were isolated and purified from different Ferula species, and were tested for their MDR reversal properties. Enhancement of doxorubicin cytotoxicity in MCF-7/Adr cells (doxorubicin resistant derivatives of MCF-7 cells overexpressing P-gp), when combined with very non-toxic concentrations of the sesquiterpene coumarins (50 µM) including umbelliprenin, farnesiferol B, farnesiferol C and lehmferin, proved significant MDR reversal activity of these coumarins. Flow cytometric efflux assay confirmed that the intracellular accumulation of Rho123 was significantly increased in MCF-7/Adr cells when treated with sesquiterpene coumarins. A deeper insight into the structure-activity relationship of sesquiterpene coumarins revealed that ring-opened drimane-type sesquiterpene coumarins including farnesiferol B, farnesiferol C and lehmferin possessed the best inhibitory effects on P-gp pump efflux and they could be considered as lead scaffolds for further structure modifications.

Synthesis and biological evaluation of novel pyridine derivatives as potential anticancer agents and phosphodiesterase-3 inhibitors.

Phosphodiesterases (PDEs) have been studied in a variety of tumours; data have suggested that the levels of PDE activities are elevated and, therefore, the ratios of cGMP to cAMP are affected. In addition, PDE inhibitors are potential targets for tumour cell growth inhibition and induction of apoptosis. Nonselective PDE inhibitors, such as theophylline or aminophylline, are known regulators of growth in a variety of carcinoma cell lines, suggesting a potential role for PDE inhibitors as anticancer drugs. In the current study, we reported the synthesis of novel derivatives of 6-aryl-4-imidazolyl-2-imino-1,2-dihydropyridine-3-carbonitriles (Ia,b,c) and their 2-oxo isosteres (IIa,b,c,d). All the compounds were evaluated for their PDE3A inhibitory effects, as well as their cytotoxic effects on MCF-7 and HeLa cell lines. Moreover, structure-activity relationships were studied. 4-(1-benzyl-2-ethylthio-5-imidazolyl)-6-(4-bromophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ib) exhibited the strongest PDE3A inhibitory effects with an IC50 of 3.76±1.03nM. Compound Ib also showed the strongest cytotoxic effects on both the HeLa and MCF-7 cells with an IC50 of 34.3±2.6µM and 50.18±1.11µM, respectively. There was a direct correlation between PDE3 inhibition and anticancer activity for the synthesised compounds. The data reported here support our view that PDEs represent promising cellular targets for antitumor treatment.

Synthesis and molecular modeling of six novel monastrol analogues: evaluation of cytotoxicity and kinesin inhibitory activity against HeLa cell line.

BACKGROUND AND THE PURPOSE OF THE STUDY: A common approach in cancer chemotherapy is development of drugs that interrupt the mitosis phase of cell division. Dimethylenastron is a known kinesin inhibitor. In this study, six novel dimethylenastron analogues (4a-f), in which 3-hydroxyphenyl substituent has been replaced with substituted benzylimidazolyl, were synthesized through Biginelli reaction. METHODS: Six novel Biginelli compounds (4a-f) were synthesized through one step Biginelli reaction of imidazole aldehydes (3a-c), dimedone and urea or thioura. In vitro cytotoxicities of prepared compounds were investigated using MTT assay. Furthermore the ELIPA kit was implemented to study inhibitory effects of synthesized compounds on ATPase activity of kinesin by measuring of organic phosphate. RESULTS: Our results indicated that analogue 4c is the most toxic and analogues 4f, 4b and dimethylenasteron were less cytotoxic in compare with other analogues. On the other hand, analogue 4a, 4b, 4c and 4e showed stronger Kinesin inhibition as compared with analogue 4f and dimethylenasteron. None of synthesized compounds were as potent kinesin inhibitor as Taxol. Docking analysis revealed that hydrogen bond formation and hydrophobic interactions were the key factors affecting inhibitory effects of these compounds. CONCLUSION: Newly synthesized compounds were found to have moderate to good cytotoxicity against HeLa cancer cell. Our results may be helpful in further design of dihydropyrimidine as potential anticancer agents.

Synthesis, Anti-Inflammatory and Anti- Nociceptive Activities and Cytotoxic Effect of Novel Thiazolidin-4-ones Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors.

OBJECTIVE(S): Nowadays, COX - 2 inhibitors such as valdecoxib are removed from the market because of their cardiovascular toxicity and their potential to increase the risk of strokes. In response to this, medicinal chemists have attempted to synthesize new classes of COX-2 Inhibitors. MATERIALS AND METHODS: In this study, three novel analogues of thiazolidin-4-ones derivatives 2a-c were synthesized. The ability of these compounds to inhibit ovine COX-1 and COX-2 (0.2- 0.8 µM) was determined using a colorimetric method. The cytotoxic effect of the synthesized compounds (25-100 M) was also investigated by measuring their cytotoxicity against Caco-2 and MCF-7 cell lines using MTT assay. Cell apoptosis was determined by flow cytometry. Writhing test (7.5-75 mg/kg) was used to examine the antinociceptive effects in mice. The effect of the analogues against acute inflammation (7.5-75 mg/kg) was also studied using xylene-induced ear edema test in mice. RESULTS: The synthesized compounds showed a weak capacity to inhibit the proliferation of Caco-2 and MCF-7 cell lines. The COX-2 inhibition potency and selectivity index for test compounds 2a-b were as follows; celecoxib > 2b > 2a. On the other hand, all three analogues exhibited strong antinociceptive activity against acetic acid-induced writhing. The anti-inflammatory and antinociceptive effects of the analogues were markedly more than positive control, celecoxib. CONCLUSION: This study demonstrates that the antinociceptive and anti-inflammatory activity profiles exhibited by the novel synthesized compounds are independent from their COX-2 inhibitory potencies. The found antinociceptive and anti-inflammatory effects can be caused by interaction with other target; independent from COX-2. Accordingly, the compounds 2a-c could serve as lead compounds to develop novel anti-inflammation and antinociceptive drugs.