Non-small Cancer Cell Lines Research Articles

Synthesis of Analogues of Natural Product ‘Antheminone A’ and Evaluation of Their Anti-Cancer Activity

Synthesis of two novel compounds (1a and 1b) derived from analogue of antheminone A (1c) and their evaluation of anti-cancer activities are hereby described. This synthesis involved a multi-step reaction sequence involving the use of natural product (-)-quinic acid (1d) and unsymmetrical dicoumarol (1e) as precursors (Figure 1). Unsymmetrical dicoumarol (1e), a potent inhibitor of NQO1 was synthesized by coupling 4-hydroxyl coumarin and an appropriate benzaldehyde. Thus, in order to facilitate drug penetration through the barriers of cell membrane to NQO1 location, compound (1e) was re-modified by coupling with an analogue of antheminone A (1c). Spectral analyses of the products were carried out in order to confirm the identity of the compounds. Interestingly, the compounds which were obtained in good to moderate yield (51-68%) exhibited toxicity against the non-small cancer cell line, A549.

Electrochemical, spectroscopic and theoretical monitoring of anthracyclines' interactions with DNA and ascorbic acid by adopting two routes: Cancer cell line studies.

Pharmacodynamic interactions of three anthracycline antibiotics namely doxorubicin (DXH), epirubicin (EpiDXH) and daunorubicin (DNR) with DNA in the absence and presence of ascorbic acid (AA) as natural additive were monitored under physiological conditions (pH = 7.4, 4.7 and T = 309.5K). Route–1 (Anthracycline–AA–DNA) and Route–2 (Anthracycline–DNA–AA) were adopted to see the interactional behavior by cyclic voltammetry (CV) and UV-visible spectroscopy. In comparison to Route–2; voltammetric and spectral responses as well as binding constant (Kb) and Gibb’s free energy change (ΔG) values revealed strongest and more favorable interaction of anthracycline–AA complex with DNA via Route–1. Kb, s (binding site sizes) and ΔG evaluated from experimental (CV, UV-Vis) and theoretical (molecular docking) findings showed enhanced binding strength of tertiary complexes as compared to binary drug–DNA complexes. The results were found comparatively better at pH 7.4. Consistency was observed in binding parameters evaluated from experimental and theoretical techniques. Diffusion coefficients (Do) and heterogeneous electron transfer rate constant (ks,h) confirmed the formation of complexes via slow diffusion kinetics. Percent cell inhibition (%Cinh) of anthracyclines for non-small cell cancer cell lines (NSCCLs) H-1299 and H-157 were evaluated higher in the presence of AA which further complimented experimental and theoretical results.

Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.

The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.

Reprogramming of cell signaling in response to MEK inhibition in non-small cell cancer (NSCLC).

e23222Background: MEK inhibitors have limited success in cancer treatment because tumors circumvent their action. Here, we report broad proteomic analysis of NSCLC cell lines after treatment with t...

Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.

The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.

Structure-activity relationship and apoptosis induction in A549 cells by the potential anticancer compound cis-bis(3-aminoflavone)dichloroplatinum(II)

cis-DDP (cis-diamminedichloroplatinum(II), CAS 15663-27-1) is widely used in chemotherapy of many types of cancer. However, besides effectiveness, it gives many side effects which limit its clinical application. Therefore, nowadays studies are focused on searching for novel analogs of cis-DDP, at least equally effective in chemotherapy but less toxic. One of them might be cis-BAFDP (cis-bis(3-aminoflavone)dichloroplatinum(II)) with one of the hydrogen atoms of the amino group of cis-DDP replaced by a flavone ring. 3-Aminoflavone (AF) which posseses the desired NH2 group has been used as non-leaving ligand. The complex has been obtained in the reaction of AF and K2PtCl4. There are no data concerning evaluation of structural studies of cis-BAFDP, the beneficial anticancer properties of which were proved in vitro and in vivo. Therefore it was worthwhile to undertake a confirmation of the chemical structure of this compound by applying various spectroscopic techniques especially because of its potential pharmacological application. With this aim in mind this compound was characterized by: IR, 1H NMR, 195Pt NMR, UV absorption and fluorescence spectroscopy. Moreover, stronger apoptosis induction by cis-BAFDP than cis-DDP in the human nonsmall cancer cell line A549 was observed using Hoechst 33258/propidium iodide double staining.

Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II

Simocyclinone D-8 (SD8), a semi-synthetic compound derived from yeast, has been shown to decrease the proliferation of MCF-7 breast cancer cells. It has been shown to be a potent bacterial DNA gyrase inhibitor, a homologue of human topoisomerase II (hTopoII). We tested SD8 activity alone and in combination with cisplatin against malignant mesothelioma (MM) and non-small cell cancer (NSCLC) cell lines. Inhibition of hTopoII supercoiling function by SD8 and a known hTopoII poison, etoposide, were done by in vitro assay using purified hTopoII and kinetoplast DNA as the substrate. The DNA products were analyzed by agarose gel electrophoresis after treatment with increasing concentrations of each drug. Mesothelioma cell lines (H2373, H2461 and H2596) and NSCLC cell lines (H2030, H460, and H2009) grown in RPMI with 10% calf serum were used. Non-malignant mesothelial cells, LP9, were grown in 1:1 ratio of MCDB:199E medium supplemented with 15% calf serum, 0.4 microg/mL hydrocortisone, and 15 ng/mL epidermal grown factor. Cell proliferation assays were performed in 96-well plates using the CCK-8 kit (Dojindo inc.). Cells were treated for 72 h with various SD8 concentrations and controls containing equal volume of the vehicle, DMSO. Treated cells were assayed for the induction of apoptosis with poly ADP-ribose polymerase-1 (PARP) cleavage assay. Biochemical assays revealed that the IC(50) for hTopoII inhibition was 100 microM for SD8 and 400 microM for etoposide. SD8 inhibited hTopoII function without inducing DNA cleavage events. SD8 inhibited the growth of NSCLC and Mesothelioma cells with IC(50) ranging from 75-125 microM. Furthermore, SD8 was not toxic to non-transformed primary mesothelial cell line, LP9 at the IC(50) doses. SD8 induced apoptosis in all cell lines tested. SD8 inhibits hTopoII in vitro without inducing DNA strands breaks and has significant activity against NSCLC and MM cell lines. While doses required for SD8 anticancer activity are unlikely to be achieved in vivo, chemical modifications to SD8 to increase its potency could lead to improved therapies for these diseases.