Beta-Lapachone Suppresses Non-small Cell Lung Cancer Proliferation through the Regulation of Specificity Protein 1

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) is the most common pathological type with a reported frequency of about 85% of all cases. Despite recent advances in therapeutic agents and targeted therapies, the prognosis for NSCLC remains poor, and therefore it is important to identify the biological targets of this complex disease since a blockade of such targets would affect multiple downstream signaling cascades. β-Lapachone (β-Lap) is an antiproliferative agent that selectively induces apoptosis-related cell death in a variety of human cancer cells. However, the mechanisms of its action require further investigation. In this study, we show that treatment with β-lap triggers apoptosis and cell-cycle arrest in two NSCLC cell lines: H1299 and NCI-H358. The transcription factor specificity protein 1 (Sp1) was markedly inhibited by β-lap in a dose-and time-dependent manner. Furthermore, β-lap modulated the protein expression levels of the Sp1 regulatory genes, including cell-cycle regulatory proteins and antiapoptotic proteins, resulting in apoptosis. Taken together, our results indicate that β-lap may be a potential antiproliferative agent candidate by inducing apoptotic cell death in NSCLC tissue through downregulation of Sp1.

β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers

“…Jeon et al . also found that β-lap inhibited cell proliferation and induced apoptosis by targeting Sp1 and apoptosis associated proteins in non-small cell lung cancer 29 . Consistent with these results, we found that β-lap exhibited strong dose-dependent inhibitory effects on MCF-7 and MDA-MB-231 cell proliferation ( P  < 0.05).…”

β-Lapachone Induces Acute Oxidative Stress in Rat Primary Astrocyte Cultures that is Terminated by the NQO1-Inhibitor Dicoumarol

“…Exposure of cancer cells to β-lap has been reported to induce toxicity and apoptosis [3][4][5][6][7][8]13] which involves intracellular superoxide formation and oxidative stress [47] due to futile redox cycling by NQO1 [10,13,47]. As also astrocytes contain NQO1 [35] the consequences of an exposure of astrocyte cultures to β-lap was investigated.…”

“…The quinone beta-lapachone (β-lap, clinical names: ARQ761 or ARQ501) has been extracted from the bark of the lapacho tree and is known to have various beneficial effects [1,2]. For example, it has frequently been applied in anti-cancer studies on cells and tissues, targeting for example prostate cancer [3], pancreatic cancer [4], lung cancer [5], breast cancer [6], melanoma [7] or astrocyte-like glioma [8]. The proposed mechanism of the antitumor action is the activation of β-lap by NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1, EC 1.6.99.2) ( Fig.…”

β-Lapachone Inhibits Lung Metastasis of Colorectal Cancer by Inducing Apoptosis of CT26 Cells

“…β-Lapachone induces cell cycle arrest and apoptosis in various cancer cells, and several mechanisms have been reported for the anti-proliferative effects of β-lapachone. 46 - 49 β-Lapachone, known as an NADPH quinone oxidoreductase 1 (NQO1) regulator, triggered necroptosis through the NQO1-dependent, reactive oxygen species–mediated receptor-interacting protein kinase 1–PARP1–apoptosis-inducing factor pathway in human hepatic adenocarcinoma SK-Hep1 cells. 46 Additionally, inactivation of the phosphoinositide 3-kinase/Akt signaling pathway was found to be related to β-lapachone-induced apoptosis and growth inhibition of human gastric carcinoma AGS cells.…”

“… 47 Specificity protein 1 (Sp1) is a constitutive transcription factor involved in the regulation of apoptosis in cancer cells. 48 , 49 β-Lapachone modulated the transactivation of Sp1 and induced apoptosis through regulation of apoptosis- and cell cycle–related proteins in non–small cell lung cancer and melanoma cells. Therefore, further studies are needed to elucidate other mechanisms for the antiproliferative and antimetastatic effects of β-lapachone on CRC cells.…”