3-Oxoolean-12-en-27-oic Acid Isolated from Aceriphyllum rossii Induces Caspase-8-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

Abstract

Information on the molecular mechanisms of drug action is essential for the development of any potential chemotherapeutic. In this context, several cancer drugs have been shown to induce apoptosis in tumor cells.1) Apoptosis, known as programmed cell death, is a highly organized cell death process that is characterized by distinct morphological features, such as, cell shrinkage, chromatin condensation, plasma membrane blebbing, DNA fragmentation, and the breakdown of cells into smaller units (apoptotic bodies). 2)Many investigators have demonstrated that apoptosis is regulated by two major pathways. [3][4][5] The first pathway occurs via death receptors on the cell surface, such as, TNFR1 (tumor necrosis factor receptor 1) and Fas, the latter of which can directly activate procaspase-8 by DISC (death-inducing signaling complex), which includes the cytoplasmic tails of Fas receptors and procaspase-8.4) Caspase-8, in turn, activates the proteolytic caspase cascade that transmits and amplifies death signals by activating apoptotic executioner caspases like caspase-3 and -7. These executioner caspases then cleave several substrate proteins including poly (ADP-ribose) polymerase-1 (PARP-1), which results in the self-destruction of cells.6) Furthermore, interaction between Fas and FasL induces apoptotic cell death and altered levels of Fas/FasL expression have been implicated in the pathogenesis of diseases associated with immune regulation. 7,8) The second pathway regulates the apoptotic cascade via a convergence of signaling at mitochondria, such as, those signals mediated by Bcl-2 family proteins. This pathway involves altered mitochondrial membrane potentials, the release of cytochrome c into the cytosol, and the activation of procaspase-9, which is followed by the activations of effector caspases like caspase-3 and -7.5) The mitochondrial pathway, driven by Bcl-2 family proteins, may involves anti-apoptotic (Bcl-2 and Bcl-xL) or pro-apoptotic (Bax, Bak, and Bid), and regulates cell death by controlling mitochondrial membrane permeability during apoptosis. 9)Triterpenoids derived from plants are used for medicinal purposes in many Asian countries and some have been reported to have anti-tumor activity.10) Moreover, it was recently found that the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleane-1,9-dien-28-oate potently induces caspase-mediated apoptosis in human lung cancer cells. 11)Furthermore, it is also known that the phytoterpenoid 3-oxoolean-12-en-27-oic acid (3-OA, a pentacyclic compound) is present in Aceriphyllum rossii ENGLER (Saxifragaceae), which grows in scant amounts in damp rocky areas in valleys in the central northern region of Korea.12) During recent years, pharmacological characterizations of 3-OA have concluded that it has several biological activities, which include; the protein tyrosine phosphatase 1B inhibitory activity, 13) acylCoA:cholesterol acyltransferase (ACAT) inhibitory activity, 12) and anti-complementary activity. 14) Furthermore, it has been demonstrated that 3-OA is c...

20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway

“…activation of caspase-9 results in the activation of caspase-3, -6 and -7, which function as downstream effectors of the cell death program. caspase-3 is an executioner caspase activated by either a mitochondrial pathway involving caspase-9 or a death receptor pathway involving caspase-8 (23)(24)(25). according to the results shown in Fig.…”

“…The second pathway involves a mitochondrial pathway that causes the release of cytochrome c into the cytosol, which triggers apoptosis by activation of caspase-9 in the presence of apoptosis protease activation factor-1 (apaf-1). This in turn results in the activation of downstream caspase-3, which cleaves ParP (24,25). recent data indicate that the mitochondrial pathway is controlled and regulated by Bcl-2 family protein (5,(22)(23)(24)(25).…”

“…This in turn results in the activation of downstream caspase-3, which cleaves ParP (24,25). recent data indicate that the mitochondrial pathway is controlled and regulated by Bcl-2 family protein (5,(22)(23)(24)(25). Bcl-2 family proteins such as Bcl-2 and Bax have been identified as major regulators in controlling the release of mitochondrial cytochrome c (26).…”

Role of Pentacyclic Triterpenoids in Chemoprevention and Anticancer Treatment: An Overview on Targets and Underling Mechanisms

“…Previous in vivo and in vitro studies has been reported that in melanoma cell lines betulinic acid aggravate apoptosis and produces selective cytotoxicity to neuroectodermal tumor, including human neuroblastoma, melanoma and Ewing sarcomas [ 35 ]. In tumor cell lines like leukemia HL-60 and HeLa cells oleanolic acid encourage apoptosis [ 14 , 48 ]. 18β-Glycyrrhetinic acid has the ability to induce cancer in a dose dependent manner.…”

“…Also they have crucial role in the process of apoptosis and about 9 different types of caspases are involved in apoptic pathway, such as death receptor pathway and mitochondrial pathway ( Fig. 4 ) [ 48 ]. In apoptosis, TNFR acts as a death receptor which is activated by ligand mediated external stimuli for example, stimulation of TNF causes adapter protein recruitment that in turn activate caspases 8, an initiator caspase.…”