Search

Aims: Hypoxia is believed to be one of the key components contributing to the clinical resistance of cancer therapies. Alternative strategies are under investigation to overcome this resistance and the oncolytic virus stands amongst the others. Newcastle disease virus (NDV) has been demonstrated to possess oncolytic activity against cancer cells. The present study investigated the effects of oncolytic NDV strain AF2240 and V4-UPM on osteosarcoma cells (Saos-2) under normoxic and hypoxic conditions. Methodology and results: Results showed that the NDV strain AF2240 and V4-UPM could infect and kill normoxic and hypoxic Saos-2 cells equally well by inducing hypoxia-independent apoptosis, and S-phase cell cycle arrest under the microscopy examination, cell viability assay, Annexin V apoptosis assay and cell cycle analysis experiments. However, the Velogenic NDV strain AF2240 excelled over the lentogenic NDV V4-UPM with increased oncolytic effects in Saos-2 cells. Conclusion, significance and impact of study: In a nutshell, normoxia or hypoxia microenvironment has little effect on NDV-induced oncolysis of Saos-2 cancer cells which poses as a potential agent for the treatment of resistant cancer. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP", with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP. [ABSTRACT FROM AUTHOR]

Introduction: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) target the key DNA repair enzymes of PARP and have emerged as small molecule drugs. Recently, ruthenium(II) polypyridyl complexes (RPCs) have shown promise as anticancer candidates due to their ability to form non-covalent (reversible) interactions with DNA. Previously, we have reported the RPC [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[ 4,5-f][1,10]phenanthroline), "Ru-PIP" induce replication stress in cancer cells by stalling the DNA replication fork progression. Therefore, the rational combination of Ru-PIP with PARPi may show synergistic activities in cancer cells. In the present study, we examine the combination of Ru-PIP with the most successful PARPi to date, Olaparib for synergy in lung cancer cells. We additionally assess toxicity of the identified combination in a zebrafish embryo model. Methods: A549 cells were treated with Ru-PIP or Olaparib single agents alone or in combination and MTT assay was carried out. Synergy was determined using Chou and Talalay combination index (CI) method in which C1 < 1 represents synergy and synergy was further confirmed using clonogenic survival assay. Further acute toxicity test of the identified synergy combination on zebrafish embryos was then carried out. Results: Ru-PIP and Olaparib synergy was observed in A549 lung cancer cell line. Synergy was confirmed by loss in clonogenic potential. Moreover, acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP. Conclusion: We demonstrate that the identified synergistic Ru-PIP/Olaparib combination may potentially reduce side effects observed in single-agent therapy and thus, demonstrate new promising therapeutic strategy to combat cancer. [ABSTRACT FROM AUTHOR]

Introduction: The evaluation of drug effects in a 3D spheroids model can provide insight on the cytotoxicity and drug penetration. In addition, 3D spheroids often better recapitulate the tissue microenvironment in vivo as they mimic the complexity and heterogeneity of cellular organization in clinical tumors. Ruthenium (II) polypyridyl complexes (RPCs) have emerged as promising anticancer candidates due to their attractive DNA binding property. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new small molecule drugs that show promising therapeutic effects. Previously, we have evaluated the rationale combination of the RPC [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c] phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP" with PARP inhibitor Olaparib in 2D monolayer cell culture in which Ru-PIP/Olaparib synergy was shown. In the present study, we examine the identified synergistic Ru-PIP/Olaparib combination in 3D lung cancer spheroids to further elucidate synergy. Methods: A549 lung cancer spheroids were developed using hanging drop technique. Spheroids growth inhibition study and spheroids live/dead staining experiments were conducted to examine the cellular viability of the spheroids upon treated with Ru-PIP/Olaparib combination. Results: A549 cells formed spheroids that managed to grow in diameter in size and volume over 15 days, thereby qualifying them as a suitable 3D cell culture model. Our results show that the structural integrity of the A549 spheroids was lost after 12 days treatment with the combination, meanwhile single agents-treated spheroids remained structurally intact, although Ru-PIP single agent inhibited spheroids growth. Compared to single agents alone, the combination induced more cell death in A549 spheroids, as indicated by Calcein AM/PI staining. Conclusion: We demonstrate that the synergistic Ru-PIP/Olaparib combination is able to inhibit the growth of the more-resistant lung cancer spheroids model, showing promising therapeutic effects and merit further clinical assessment in vivo. [ABSTRACT FROM AUTHOR]

Aim: Chromones are promising for anticancer drug development. Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC 50 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC 50 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1. Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.