Annexin Proteins: Novel Promising Targets for Anticancer Drug Development

Intracellular Ca2+ signaling and Ca2+ homeostasis have long been an important subject area of cell biology. Several intracellular Ca2+ binding proteins have been demonstrated until now, and among these, annexins are characterized by their ability to interact with membrane phospholipids and they form an evolutionary conserved multigene family with the members being expressed throughout animal and plant kingdoms. Annexin proteins are defined by different structural and biochemical criteria, and this multigene family has several biological features. In certain clinical conditions, the alterations on the localization or expression levels of annexin proteins are considered as the causes of pathological results and/or sequelae of disease. So, annexin proteins are indirectly linked to severe human diseases such as cardiovascular disease and cancer. Since annexin proteins are known to play roles in cancer, the researches are focused on defining the clinical significance of certain annexin proteins in cancer development and by the way anticancer treatments in the last decades. This chapter presents detailed information about annexin proteins and the studies on anticancer drug development targeting certain annexins. The studies denominate that targeting of certain annexin proteins reduces tumorigenesis and therapeutic resistance. So, annexin proteins have growing importance for anticancer drug development

Seseli petraeum M. Bieb. (Apiaceae) Significantly Inhibited Cellular Growth of A549 Lung Cancer Cells through G0/G1 Cell Cycle Arrest.

Seseli L. is an important genus of the Apiaceae family, with a large number of aromatic species. It is used in traditional medicine extensively, but there is quite limited information on their phytochemicals and biological activities. Seseli petraeum M. Bieb. grows in Northern Anatolia, and there are no phytochemical studies on this species. In the present study, we aimed to investigate the effect of the extracts of S. petraeum on A549 lung cancer cell proliferation. For this purpose, the antiproliferative effect was determined via MTT assay, and the extracts obtained from the root of S. petraeum showed a significant inhibitory effect on cell proliferation. The hexane extract of the root exhibited potent inhibition on A549 cancer cell growth at the 24th hour with 3.432 mg/mL IC50 value. The results also showed that the hexane extract had displayed cytotoxic effect through an arrest at the G0/G1 phase of the cell cycle and induced apoptosis as well as DNA damage of A549 cells. Consequently, this study demonstrated the antiproliferative potential of the extracts from S. petraeum, especially hexane extract from the roots. Further studies are required to identify the mechanisms underlying these effects

Seseli petraeum M. Bieb. (Apiaceae) Significantly Inhibited Cellular Growth of A549 Lung Cancer Cells through G0/G1 Cell Cycle Arrest.

Seseli L. is an important genus of the Apiaceae family, with a large number of aromatic species. It is used in traditional medicine extensively, but there is quite limited information on their phytochemicals and biological activities. Seseli petraeum M. Bieb. grows in Northern Anatolia, and there are no phytochemical studies on this species. In the present study, we aimed to investigate the effect of the extracts of S. petraeum on A549 lung cancer cell proliferation. For this purpose, the antiproliferative effect was determined via MTT assay, and the extracts obtained from the root of S. petraeum showed a significant inhibitory effect on cell proliferation. The hexane extract of the root exhibited potent inhibition on A549 cancer cell growth at the 24th hour with 3.432 mg/mL IC50 value. The results also showed that the hexane extract had displayed cytotoxic effect through an arrest at the G0/G1 phase of the cell cycle and induced apoptosis as well as DNA damage of A549 cells. Consequently, this study demonstrated the antiproliferative potential of the extracts from S. petraeum, especially hexane extract from the roots. Further studies are required to identify the mechanisms underlying these effects

Seseli petraeum M. Bieb. (Apiaceae) Significantly Inhibited Cellular Growth of A549 Lung Cancer Cells through G0/G1 Cell Cycle Arrest.

Seseli L. is an important genus of the Apiaceae family, with a large number of aromatic species. It is used in traditional medicine extensively, but there is quite limited information on their phytochemicals and biological activities. Seseli petraeum M. Bieb. grows in Northern Anatolia, and there are no phytochemical studies on this species. In the present study, we aimed to investigate the effect of the extracts of S. petraeum on A549 lung cancer cell proliferation. For this purpose, the antiproliferative effect was determined via MTT assay, and the extracts obtained from the root of S. petraeum showed a significant inhibitory effect on cell proliferation. The hexane extract of the root exhibited potent inhibition on A549 cancer cell growth at the 24th hour with 3.432 mg/mL IC50 value. The results also showed that the hexane extract had displayed cytotoxic effect through an arrest at the G0/G1 phase of the cell cycle and induced apoptosis as well as DNA damage of A549 cells. Consequently, this study demonstrated the antiproliferative potential of the extracts from S. petraeum, especially hexane extract from the roots. Further studies are required to identify the mechanisms underlying these effects

Synthesis and potent cytotoxicity of some novel imidazopyridine derivatives against MCF-7 human breast adenocarcinoma cell line

A series of novel 2-phenyl-3H-imidazo[4,5-b]pyridines and 2-phenyl-3H-imidazo[4,5-c]pyridines and their precursors were synthesized. Their in vitro cytotoxicity against MCF-7 human breast adenocarcinoma cell line has been investigated, and some of the tested compounds have shown high cytotoxic activity against MCF-7 cells. N-Hydroxy-4-(3H-imidazo[4,5-b]pyridin-2-yl)benzenecarboximidamide was the most active compound with IC50 equal to 0.082 mu M, which is an activity almost as high as that of a commonly used anticancer drugs docetaxel and imatinib mesylate

Receptor Tyrosine Kinase Inhibitory Activities and Molecular Docking Studies of Some Pyrrolo[2, 3-d]pyrimidine Derivatives: Receptor tyrosine kinase inhibitory effects of some pyrrolopyrimidine derivatives

In this study, we aimed to determine VEGFR-2, EGFR and PDGFR-β tyrosine kinase inhibitory activities of some pyrrolo[2,3-d]pyrimidine derivatives previously synthesized and showed potent cytotoxic and apoptotic effects against several cancer cell lines by our group and to evaluate the relationships between inhibitory activities and binding properties of the active compounds by molecular docking studies. VEGFR-2, EGFR ve PDGFR-β tyrosine kinases inhibitory activities of the tested compounds were determined using KDR Kinase Enzyme System Analysis Kit (Promega, #V2681), EGFR Kinase Enzyme System Analysis Kit (Promega,#V3831) and PDGFR-β Kinase Enzyme System Analysis Kits (Promega, #V3731) according to the manufacturer’s instructions. The molecular docking studies were performed using Autodock vina program.Compounds 9a, 9b and 11b exhibited the weak inhibitory activities against VEGFR-2, EGFR and PDGFR-β,respectively. Molecular docking studies showed that one or two hydrogen bonding interactions were found between compounds 9a, 9b, 11b and VEGFR-2, EGFR, PDGFR-β tyrosine kinases. Biological activity and molecular docking results revealed that interactions of compounds with target protein active sites are not enough to obtain potent RTK inhibitory activity. It is necessary to design some compounds showing more interactions with the target proteins to obtain better activity results

Cytotoxic and apoptotic effects of novel pyrrolo[2,3-d]pyrimidine derivatives containing urea moieties on cancer cell lines

Background: Pyrrolo[2,3-d]pyrimidines have been recently reported to have anticancer activities through inhibition of different targets such as, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, Janus Kinase (JAK), mitotic checkpoint protein kinase (Mps1), carbonic anhydrase, MDM-2. On the other hand, aryl urea moieties which are found in some tyrosine kinase inhibitors such as Sorafenib and Linifanib have aroused recent attention as responsible for anticancer activities. The aims of this paper are to synthesize pyrrolo[2,3-d]pyrimidine derivatives containing urea moiety and evaluate their anti-cancer activity against human lung cancer cell line (A549), prostate cancer cell line (PC3), human colon cancer cell line (SW480) and human breast cancer cell line (MCF-7). Methods: A series of new pyrrolo[2,3-d]pyrimidines containing urea moieties have been synthesized as Scheme 1. In vitro cytotoxicity of target compounds were evaluated against, SW480, PC3, A549 and MCF-7 human cancer cell lines using a MTT assay. In order to evaluate the mechanism of cytotoxic activity of compounds 9e, 10a and 10b, having the best cytotoxic activity, Annexin V binding assay, cell cycle analysis and western blot analysis were performed. Results: Among the target compounds, 10a (IC50 = 0.19 mu M) was found to be the most potent derivative against PC3 cells. Compound 10b and 9e showed the strong cytotoxic activity against MCF-7 and A549 cells with IC50 value of 1.66 mu M and 4.55 mu M, respectively. Flow cytometry data suggest that the cytotoxic activity of the compounds on cancer cells might be mediated by apoptosis revealing a significant increase in the percentage of late apoptotic cells and causing a cell cycle arrest at different stages. Western blot analysis of apoptosis marker demonstrated that these compounds induce apoptosis through the intrinsic pathway. Conclusion: Compound 9e displayed the strongest cytotoxicity against A549 cancer cell line, and induced late apoptosis in A549, as confirmed by cell cycle arrest in G0/G1 phase. In addition, compound 9e reduced expression of the anti-apoptotic protein Bcl-2 and enhanced expression of the pro-apoptotic protein Bax, besides increased caspase-9 and caspase-3, as well as cleavage of PARP levels. These results suggest that compound 9e showed a cytotoxic effect in A549 cells through activation of the mitochondrial apoptotic pathway. Further studies will be undertaken in our laboratory to improve cytotoxic activity of compound 9e and to identify the biological targets of 9e which are responsible for anticancer activity