Ursolic Acid Induces Apoptotic Cell Death Through AIF and Endo G Release Through a Mitochondria-dependent Pathway in NCI-H292 Human Lung Cancer Cells In Vitro

Abstract

Background/Aim: Ursolic acid (UA), a triterpene compound present in natural plants, has been shown to induce cytotoxic effects on many human cancer cells through induction of cell-cycle arrest and apoptosis. This study investigated the effects of UA on human lung cancer NCI-H292 cells in vitro. Materials and Methods: Flow cytometric assay was used to measure the percentage of cell viability, apoptotic cell death by double staining of annexin V and propidium iodide (PI), production of reactive oxygen species (ROS) and Ca 2+ , and mitochondriaI membrane potential (Ψ m). UA-induced chromatin condensation and DNA fragmentation were examined by 4',6-diamidino-2-phenylindole staining and DNA gel electrophoresis, respectively. Western blotting was used to examine the changes of apoptosis-associated protein expression in NCI-H292 cells. Results: UA reduced cell viability and induced apoptotic cell death. UA increased Ca 2+ production, reduced Ψ m , but did not affect ROS production in NCI-H292 cells. UA increased apoptosis-inducing factor (AIF) and endonuclease G in NCI-H292 cells. Conclusion: Based on these observations, we suggest UA induces apoptotic cell death via AIF and Endo G release through a mitochondria-dependent pathway in NCI-H292 cells. Lung cancer is the leading cause of cancer-associated death worldwide (1) and divided into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The most common type is NSCLC accounting for about 80-85% (2, 3), with poor prognosis and a high incidence of recurrence (4). NSCLC includes adenocarcinoma, squamous cell carcinoma, and large-cell carcinomas (5). Although advanced diagnostics and therapeutics have been developed, the treatment and outcome of lung cancer is still unsatisfactory (4, 6-8). Characteristics of cancer include uncontrolled cell-cycle progression and deregulation of apoptosis. One of the therapeutic strategies for chemotherapy is to induce cancer cell apoptosis. Apoptosis plays a critical role in the balance between cellular replication and death, in particular for elimination of unwanted, damaged or infected cells (9, 10). Much evidence has shown that chemotherapy drugs in clinical used for patients with cancer via the activation of apoptotic pathways in cancer cells (11-13). When the mitochondria membrane potential (Ψ m) decreases, cytochrome c binds to 383 This article is freely accessible online.

WITHDRAWN: Sambucus Ebulus Fruits Extract Ameliorates Eosinophilic Nasal Polyposis: An in vitro Study

“…Ursolic acid has been reported to inhibit the in ammatory factors TNF-α and IL6, LOX-1, VCAM-1, ICAM, IL5, IL13 and IL17 [30]. Another study shows that ursolic acid increases apoptosis in lung cancer cells [31]. In addition, it is also reported that UA via decreasing Bcl-2, Mcl-1, TCTP expression and increasing apoptotic proteins such as TNF-α, Fas, FADD and BAX results in activation of caspase-3 and PARP which induces apoptosis of the liver cancer cells.…”

Ursolic acid suppresses the biological function of osteosarcoma cells

“…1A. The MTT assay suggested that ursolic acid inhibited the proliferation of HOS cells in a concentration-dependent manner; through the calculation method of predecessors (14), the IC 50 of ursolic acid was ~35 µmol/l ( Fig. 1B and C).…”

<p>The Analysis of the Anti-Tumor Mechanism of Ursolic Acid Using Connectively Map Approach in Breast Cancer Cells Line MCF-7</p>

“…7,8 Several studies have confirmed that UA has shown strong anticancer effects against lung cancer, BC, and so on. 9,10 Yeh et al investigated that UA inhibited cancer cell invasion, migration, and proliferation in MDA-MB-231 via down-regulating u-PA and MMP-2 expression, and upregulating the expression of PAI-I and TIMP-2. 11 UA has also been reported to reduce the phosphorylation of AKT/ mTOR signaling for modulating proliferation and apoptosis.…”