Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species

Khz is a compound derived from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia that inhibits the growth of cancer cells. The results of the present study show that Khz induced apoptosis preferentially in transformed cells and had only minimal effects on non-transformed cells. Furthermore, Khz induced apoptosis by increasing the intracellular Ca2+ concentration ([Ca2+]i) and activating JNK to generate reactive oxygen species (ROS) via NADPH oxidase and the mitochondria. Khz-induced apoptosis was caspase-dependent and occurred via a mitochondrial pathway. ROS generation by NADPH oxidase was critical for Khz-induced apoptosis, and although mitochondrial ROS production was also required, it appeared to occur secondary to ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the translocation of regulatory subunits p47phox and p67phox to the cell membrane and was necessary for ROS generation by Khz. Khz triggered a rapid and sustained increase in [Ca2+]i, which activated JNK. JNK plays a key role in the activation of NADPH oxidase because inhibition of its expression or activity abrogated membrane translocation of the p47phox and p67phox subunits and ROS generation. In summary, these data indicate that Khz preferentially induces apoptosis in cancer cells, and the signaling mechanisms involve an increase in [Ca2+]i, JNK activation, and ROS generation via NADPH oxidase and mitochondria.

• Publication year

  2012

• Venue

  PLoS ONE

• Publication date

  2012-10-08

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0046208PMID 23056263PMCID 3466234
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cytotoxic steroids from Polyporus umbellatus.

  2010cited by this paper
• Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells.

  2010cited by this paper
• PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death

  2009cited by this paper
• NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation

  2009cited by this paper
• Ganoderma lucidum: a potent pharmacological macrofungus.

  2009cited by this paper
• Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling.

  2008cited by this paper
• Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model

  2008cited by this paper
• Mechanisms of Cell Death in Oxidative Stress

  2007cited by this paper
• Mitochondria, oxidative stress and cell death

  2007cited by this paper
• Nox2, Ca2+, and Protein Kinase C Play a Role in Angiotensin II–Induced Free Radical Production in Nucleus Tractus Solitarius

  2006cited by this paper
• Comparative Studies of Various Ganoderma Species and Their Different Parts with Regard to Their Antitumor and Immunomodulating Activities In Vitro

  2006cited by this paper
• NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac muscle cells: effects of apocynin.

  2006cited by this paper
• NADPH oxidase and apoptosis in cerulein-stimulated pancreatic acinar AR42J cells.

  2005cited by this paper
• Antitumor Activity and Underlying Mechanisms of Ganopoly, The Refined Polysaccharides Extracted from Ganoderma Lucidum, in Mice

  2005cited by this paper
• Apoptosis pathways in cancer and cancer therapy

  2004cited by this paper
• Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms.

  2004cited by this paper
• BAX and BAK Regulation of Endoplasmic Reticulum Ca2+: A Control Point for Apoptosis

  2003cited by this paper
• Inhibition of Mitochondrial Respiration

  2003cited by this paper
• Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents.

  2003cited by this paper
• Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane‐ and granule‐localized NADPH‐oxidase

  2002cited by this paper
• Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis.

  2002cited by this paper
• The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells.

  2002cited by this paper
• Mitochondrial reactive oxygen species in cell death signaling.

  2002cited by this paper
• Enhanced ROS Production in Oncogenically Transformed Cells Potentiates c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase Activation and Sensitization to Genotoxic Stress

  2001cited by this paper
• Modification by Tissue Glutathione Levels Noninvasive Imaging of Tumor Redox Status and Its Updated Version

  2001cited by this paper
• Selective Targeting of a Redox-active Ubiquinone to Mitochondria within Cells

  2001cited by this paper
• Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective.

  1999cited by this paper
• The role of calcium in apoptosis.

  1998cited by this paper
• The role of calcium in apoptosis

  1998cited by this paper
• Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells.

  1998cited by this paper
• Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells.

  1997cited by this paper
• Chemotherapy-induced apoptosis.

  1997cited by this paper
• Implication of Mitochondrial Hydrogen Peroxide Generation in Ceramide-induced Apoptosis*

  1997cited by this paper
• Reactive oxygen species and programmed cell death.

  1996cited by this paper
• Programmed cell death and Bcl-2 protection in very low oxygen

  1995cited by this paper
• Oxidative stress as a mediator of apoptosis.

  1994cited by this paper
• Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation.

  1992cited by this paper
• A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells.

  1992cited by this paper
• Br. J. Cancer

  1991cited by this paper
• Apoptosis: mechanisms and roles in pathology.

  1991cited by this paper

• Insight into the nuclear distribution patterns of conidia and the asexual life cycle of Polyporus umbellatus.

  2024cites this paper
• Phytochemistry and bioactivities of the main constituents of Polyporus umbellatus (Pers.) Fries.

  2022cites this paper
• Ganoderma and Health: Pharmacology and Clinical Application

  2019influential citation
• Cellular and Molecular Mechanism of Ganoderma (Lingzhi) Against Tumor.

  2019cites this paper
• Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy.

  2017cites this paper
• Induction of apoptosis in MCF‑7 human breast cancer cells by Khz (fusion of Ganoderma lucidum and Polyporus umbellatus mycelium).

  2016cites this paper
• Polyporus umbellatus, an Edible-Medicinal Cultivated Mushroom with Multiple Developed Health-Care Products as Food, Medicine and Cosmetics: A Review

  2015cites this paper
• Khz (Fusion Product of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis in Human Colon Carcinoma HCT116 Cells, Accompanied by an Increase in Reactive Oxygen Species, Activation of Caspase 3, and Increased Intracellular Ca2+

  2015cites this paper
• Researching glutamate – induced cytotoxicity in different cell lines: a comparative/collective analysis/study

  2015cites this paper
• Khz-cp (crude polysaccharide extract obtained from the fusion of Ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis by increasing intracellular calcium levels and activating P38 and NADPH oxidase-dependent generation of reactive oxygen species in SNU-1 cells

  2014cites this paper
• Inhibition of VDAC1 prevents Ca2+-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages

  2014cites this paper
• Khz (fusion of ganoderma lucidum and Polyporus umbellatus mycelia) induces apoptosis in A549 human lung cancer cells by generating reactive oxygen species and decreasing the mitochondrial membrane potential

  2014cites this paper
• Glucocerebrosidase mutations and Parkinson's disease

  2013cites this paper
• The Hep573 Study: a randomised, double-blind, placebo-controlled clinical trial of silymarin alone, and silymarin combined with antioxidants in chronic hepatitis C | NOVA. The University of Newcastle's Digital Repository

  2013cites this paper
• The involvement of endoplasmic reticulum stress in bile acid-induced hepatocellular injury

  2013cites this paper
• Anticancer Activity of Amauroderma rude

  2013cites this paper
• Traditional uses, phytochemistry, pharmacology, pharmacokinetics and quality control of Polyporus umbellatus (Pers.) Fries: a review.

  2013cites this paper