Metal-induced apoptosis: mechanisms.

The past decade has seen an intense focus on mechanisms of apoptosis. Many important observations on the various signaling pathways mediating apoptotic cell death have been made and our understanding of the importance of apoptosis in both normal growth and development and pathophysiology has greatly increased. In addition, mechanisms of metal-induced toxicity continue to be of interest given the ubiquitous nature of these contaminants. The purpose of this review is to summarize our current understanding of the apoptotic pathways that are initiated by metals, mainly established (arsenic, cadmium, chromium, nickel, beryllium) and possible (lead, antimony, cobalt) human carcinogens. Increased understanding of metal-induced apoptosis is critical to illuminate mechanisms of metal-induced carcinogenesis, as well as the potential of metal species (arsenic) as chemotherapeutic agents.

[1]  T. Nagata,et al.  Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria‐mediated cell death in TCR‐ and dexamethasone‐stimulated thymocytes , 2001, European journal of immunology.

[2]  Y. Shen,et al.  p53-dependent apoptosis pathways. , 2001, Advances in cancer research.

[3]  P. Prieto,et al.  Sensitive endpoints for evaluating cadmium-induced acute toxicity in LLC-PK1 cells. , 2003, Toxicology.

[4]  D. Ryberg,et al.  Mechanisms of chromium toxicity in mitochondria. , 1990, Chemico-biological interactions.

[5]  S. Das Gupta,et al.  Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants. , 2002, Toxicology letters.

[6]  O. Pellegrini,et al.  Cadmium induced apoptosis in a human T cell line , 1994 .

[7]  Mark H Ellisman,et al.  Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  V. Castranova,et al.  Reduction of chromium(VI) and its relationship to carcinogenesis. , 1999, Journal of toxicology and environmental health. Part B, Critical reviews.

[9]  O. Fardel,et al.  Potassium antimonyl tartrate induces reactive oxygen species-related apoptosis in human myeloid leukemic HL60 cells. , 2002, International journal of oncology.

[10]  S. Patierno,et al.  Metals and disorders of cell accumulation: modulation of apoptosis and cell proliferation. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[11]  Wilfred W. Li,et al.  The tumor promoter arsenite stimulates AP‐1 activity by inhibiting a JNK phosphatase. , 1996, The EMBO journal.

[12]  V. Fadok,et al.  Beryllium-stimulated apoptosis in macrophage cell lines. , 2000, Toxicology.

[13]  S. Hilsenbeck,et al.  Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. , 2003, Blood.

[14]  C. Klaassen,et al.  Cadmium-induced apoptosis in mouse liver. , 1998, Toxicology and applied pharmacology.

[15]  M. Lag,et al.  Cadmium-induced apoptosis of primary epithelial lung cells: Involvement of Bax and p53, but not of oxidative stress , 2004, Cell Biology and Toxicology.

[16]  Xianglin Shi,et al.  Cell apoptosis induced by carcinogenic metals. , 2001 .

[17]  K. Fung,et al.  Effect of arsenic trioxide on human hepatocellular carcinoma HepG2 cells: inhibition of proliferation and induction of apoptosis. , 2002, Life sciences.

[18]  N. Haramaki,et al.  DNA single-strand breaks and cytotoxicity induced by chromate(VI), cadmium(II), and mercury(II) in hydrogen peroxide-resistant cell lines. , 1994, Environmental health perspectives.

[19]  Y. Rojanasakul,et al.  Role of Reactive Oxygen Species and p53 in Chromium(VI)-induced Apoptosis* , 1999, The Journal of Biological Chemistry.

[20]  C. Zazueta,et al.  Possible involvement of the adenine nucleotide translocase in the activation of the permeability transition pore induced by cadmium. , 2000, The international journal of biochemistry & cell biology.

[21]  H. Saito,et al.  Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis , 2000, Leukemia.

[22]  A. Hartwig,et al.  Induction and repair inhibition of oxidative DNA damage by nickel(II) and cadmium(II) in mammalian cells. , 1997, Carcinogenesis.

[23]  E. Bröcker,et al.  Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt. , 1995, Journal of immunology.

[24]  Jiping Zeng,et al.  Involvement of caspase‐3 and p38 mitogen‐activated protein kinase in cobalt chloride‐induced apoptosis in PC12 cells , 2002, Journal of neuroscience research.

[25]  J. Orenstein,et al.  Induction of apoptotic cell death by particulate lead chromate: differential effects of vitamins C and E on genotoxicity and survival. , 1997, Toxicology and applied pharmacology.

[26]  J. Shen,et al.  Arsenic trioxide induces apoptosis of oesophageal carcinoma in vitro. , 1999, International journal of molecular medicine.

[27]  M. Kazanietz,et al.  Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells* , 2000, The Journal of Biological Chemistry.

[28]  V. Fadok,et al.  Beryllium induces apoptosis in human lung macrophages. , 2002, Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG.

[29]  D. Heimbrook,et al.  Therapeutic intervention and signaling. , 1998, Current opinion in cell biology.

[30]  M. Matsuoka,et al.  Involvement of the extracellular signal-regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRF-CEM cells. , 2000, Biochemical pharmacology.

[31]  E. Belyaeva,et al.  Bivalent Metal Ions Modulate Cd2+ Effects on Isolated Rat Liver Mitochondria , 2001, Journal of bioenergetics and biomembranes.

[32]  P. Joseph,et al.  Gene expression profile in BALB/c‐3T3 cells transformed with beryllium sulfate , 2001, Molecular carcinogenesis.

[33]  Weiya Ma,et al.  Activation of PKC is required for arsenite-induced signal transduction. , 2000, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[34]  M. Biagioli,et al.  Cadmium-induced apoptosis in C6 glioma cells: Mediation by caspase 9-activation , 2002, Biometals.

[35]  Shigeomi Shimizu,et al.  Bcl‐2 family: Life‐or‐death switch , 2000, FEBS letters.

[36]  M. Athar,et al.  Evidence for the involvement of hydroxyl radicals in nickel mediated enhancement of lipid peroxidation: implications for nickel carcinogenesis. , 1987, Biochemical and biophysical research communications.

[37]  B. Lau,et al.  Protective effect of gypenosides against oxidative stress in phagocytes, vascular endothelial cells and liver microsomes. , 1993, Cancer biotherapy.

[38]  D. Srivastava,et al.  Lead-induced alterations in retinal cGMP phosphodiesterase trigger calcium overload, mitochondrial dysfunction and rod photoreceptor apoptosis. , 1998, Toxicology letters.

[39]  D. Beyersmann,et al.  Cadmium, gene regulation, and cellular signalling in mammalian cells. , 1997, Toxicology and applied pharmacology.

[40]  Y. Huang,et al.  Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia , 2000, Leukemia.

[41]  Y. Seo,et al.  Nickel (II)-induced apoptosis and G2/M enrichment , 1998, Experimental & Molecular Medicine.

[42]  S. Stohs,et al.  Cadmium-induced production of superoxide anion and nitric oxide, DNA single strand breaks and lactate dehydrogenase leakage in J774A.1 cell cultures. , 1996, Toxicology.

[43]  Z. Xia,et al.  Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. , 2001, Toxicology and applied pharmacology.

[44]  Yong-kui,et al.  Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. , 1999, Journal of the National Cancer Institute.

[45]  V. Cryns,et al.  Proteases to die for. , 1998, Genes & development.

[46]  Y. Akao,et al.  Arsenic trioxide induces apoptosis in neuroblastoma cell lines through the activation of caspase 3 in vitro , 1999, FEBS letters.

[47]  M. Gorospe,et al.  Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin of CASPASE-10 in Acute Promyelocytic Leukemia Cells* , 2002, The Journal of Biological Chemistry.

[48]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[49]  B. Chernyak,et al.  Modulation of the Mitochondrial Permeability Transition Pore by Pyridine Nucleotides and Dithiol Oxidation at Two Separate Sites (*) , 1996, The Journal of Biological Chemistry.

[50]  Wei Liu,et al.  Arsenite Induces Apoptosis of Murine T Lymphocytes Through Membrane Raft-Linked Signaling for Activation of c-Jun Amino-Terminal Kinase1 , 2000, The Journal of Immunology.

[51]  Guido Kroemer,et al.  Mitochondria and programmed cell death: back to the future , 1996, FEBS letters.

[52]  R. Klein,et al.  Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of caspases , 1999, Medical oncology.

[53]  Margot Thome,et al.  Inhibition of death receptor signals by cellular FLIP , 1997, Nature.

[54]  J. Chiu,et al.  Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. , 1999, Toxicology.

[55]  L. Fritz,et al.  Bcl-xL Functions Downstream of Caspase-8 to Inhibit Fas- and Tumor Necrosis Factor Receptor 1-induced Apoptosis of MCF7 Breast Carcinoma Cells* , 1998, The Journal of Biological Chemistry.

[56]  Jean-Claude Martinou,et al.  Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions , 1998, The Journal of cell biology.

[57]  A. Bode,et al.  Transactivation of AP-1 in AP-1-luciferase reporter transgenic mice by arsenite and arsenate. , 2001, Anticancer Research.

[58]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

[59]  T. Sakurai,et al.  Dimethylarsinic acid causes apoptosis in HL-60 cells via interaction with glutathione , 1996, Archives of Toxicology.

[60]  W. Zou,et al.  Cobalt chloride induces PC12 cells apoptosis through reactive oxygen species and accompanied by AP‐1 activation , 2001, Journal of neuroscience research.

[61]  Jiahuai Han,et al.  The Stress Inducer Arsenite Activates Mitogen-activated Protein Kinases Extracellular Signal-regulated Kinases 1 and 2 via a MAPK Kinase 6/p38-dependent Pathway* , 1998, The Journal of Biological Chemistry.

[62]  F. Thévenod,et al.  Up-regulation of Multidrug Resistance P-glycoprotein via Nuclear Factor-κB Activation Protects Kidney Proximal Tubule Cells from Cadmium- and Reactive Oxygen Species-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[63]  G. Salvesen,et al.  The Regulation of Anoikis: MEKK-1 Activation Requires Cleavage by Caspases , 1997, Cell.

[64]  Z. Dong.  The molecular mechanisms of arsenic-induced cell transformation and apoptosis. , 2002, Environmental health perspectives.

[65]  D. E. Pritchard,et al.  Cyclosporin A inhibits chromium(VI)-induced apoptosis and mitochondrial cytochrome c release and restores clonogenic survival in CHO cells. , 2000, Carcinogenesis.

[66]  C. Kuo,et al.  Antimony trichloride induces DNA damage and apoptosis in mammalian cells. , 1998, Toxicology.

[67]  R. Zoncu,et al.  Cadmium-induced apoptosis in murine fibroblasts is suppressed by Bcl-2 , 2001, Archives of Toxicology.

[68]  Masashi Kobayashi,et al.  Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[69]  S. De Flora,et al.  Induction of apoptosis in the lung but not in the liver of rats receiving intra-tracheal instillations of chromium(VI). , 2002, Carcinogenesis.

[70]  Jiahuai Han,et al.  Cell Stress and MKK6b-mediated p38 MAP Kinase Activation Inhibit Tumor Necrosis Factor-induced IκB Phosphorylation and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[71]  C. J. Roberge,et al.  Toxaphene, but not beryllium, induces human neutrophil chemotaxis and apoptosis via reactive oxygen species (ROS): involvement of caspases and ROS in the degradation of cytoskeletal proteins. , 2002, Clinical immunology.

[72]  S. Waxman,et al.  Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. , 1999, Blood.

[73]  D. Bagchi,et al.  Oxidative mechanisms in the toxicity of metal ions. , 1995, Free radical biology & medicine.

[74]  H. Ichijo,et al.  Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1. , 2001, Journal of biochemistry.

[75]  S. Korsmeyer,et al.  BCL-2 family members and the mitochondria in apoptosis. , 1999, Genes & development.

[76]  S H Kaufmann,et al.  Mammalian caspases: structure, activation, substrates, and functions during apoptosis. , 1999, Annual review of biochemistry.

[77]  D. Menendez,et al.  Induction of p53 protein expression by sodium arsenite. , 1997, Mutation research.

[78]  S. Yuen,et al.  Arsenic trioxide induces apoptosis in human gastric cancer cells through up‐regulation of P53 and activation of caspase‐3 , 2001, International journal of cancer.

[79]  M. Fu,et al.  Arsenic trioxide induces apoptosis of HPV16 DNA‐immortalized human cervical epithelial cells and selectively inhibits viral gene expression , 1999, International journal of cancer.

[80]  Jia-Ling Yang,et al.  Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. , 2000, Carcinogenesis.

[81]  D. E. Pritchard,et al.  Chromium(VI) Induces p53‐Dependent Apoptosis in Diploid Human Lung and Mouse Dermal Fibroblasts , 2000, Molecular carcinogenesis.

[82]  M. Waalkes,et al.  Induction of apoptosis in cells by cadmium: quantitative negative correlation between basal or induced metallothionein concentration and apoptotic rate. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[83]  A. Strasser,et al.  Ionizing Radiation and Chemotherapeutic Drugs Induce Apoptosis in Lymphocytes in the Absence of FAS or Fadd/Mort1 Signaling Implications for Cancer Therapy , 2000 .

[84]  K. Jan,et al.  Reactive oxygen species are involved in nickel inhibition of DNA repair , 1997, Environmental and molecular mutagenesis.

[85]  G. Kroemer,et al.  Organelle-specific initiation of cell death pathways , 2001, Nature Cell Biology.

[86]  J. Frydman,et al.  Heme oxygenase induction by CoCl2, Co-protoporphyrin IX, phenylhydrazine, and diamide: evidence for oxidative stress involvement. , 1991, Archives of biochemistry and biophysics.

[87]  M. Tirmenstein,et al.  Antimony-induced oxidative stress and toxicity in cultured cardiac myocytes. , 1995, Toxicology and applied pharmacology.

[88]  D. E. Pritchard,et al.  Chromium-induced genotoxicity and apoptosis: relationship to chromium carcinogenesis (review). , 1998, Oncology reports.

[89]  J. Savill.  Apoptosis in resolution of inflammation , 1997, Journal of leukocyte biology.

[90]  Weiya Ma,et al.  Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway. , 1999, Cancer research.

[91]  J. Pourahmad,et al.  Hepatocyte lysis induced by environmental metal toxins may involve apoptotic death signals initiated by mitochondrial injury. , 2001, Advances in experimental medicine and biology.

[92]  Y. Seo,et al.  Nickel(II)-induced apoptosis in murine T cell hybridoma cells is associated with increased fas ligand expression. , 2002, Toxicology and applied pharmacology.

[93]  M. Kubbutat,et al.  Regulation of p53 Function and Stability by Phosphorylation , 1999, Molecular and Cellular Biology.

[94]  Xu Luo,et al.  Endonuclease G is an apoptotic DNase when released from mitochondria , 2001, Nature.

[95]  P. Vandenabeele,et al.  Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation , 2001, Cell Death and Differentiation.

[96]  J. Mieyal,et al.  Acute Cadmium Exposure Inactivates Thioltransferase (Glutaredoxin), Inhibits Intracellular Reduction of Protein-glutathionyl-mixed Disulfides, and Initiates Apoptosis* , 2000, The Journal of Biological Chemistry.

[97]  G. M. Ledda-Columbano,et al.  Occurrence of cell death (apoptosis) during the involution of liver hyperplasia. , 1985, Laboratory investigation; a journal of technical methods and pathology.

[98]  E. Sulpice,et al.  Effect of arsenic trioxide on viability, proliferation, and apoptosis in human megakaryocytic leukemia cell lines. , 1999, Experimental hematology.

[99]  Xianglin Shi,et al.  Intracellular signal transduction of cells in response to carcinogenic metals. , 2002, Critical reviews in oncology/hematology.

[100]  T. Kamińska,et al.  The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures. , 2000, Toxicology.

[101]  S. Wong,et al.  Toxicity to alveolar macrophages in rats following parenteral injection of nickel chloride. , 1989, Toxicology and applied pharmacology.

[102]  K. W. Kim,et al.  Cadmium induces caspase-mediated cell death: suppression by Bcl-2. , 2000, Toxicology.

[103]  K. Kasprzak,et al.  Cell cycle arrest, apoptosis and p53 expression in nickel(II) acetate-treated Chinese hamster ovary cells. , 1998, Carcinogenesis.

[104]  T. Aiuchi,et al.  Apoptosis induced by arsenic trioxide in leukemia U937 cells is dependent on activation of p38, inactivation of ERK and the Ca2+‐dependent production of superoxide , 2001, International journal of cancer.

[105]  Lihua He,et al.  Lead and Calcium Produce Rod Photoreceptor Cell Apoptosis by Opening the Mitochondrial Permeability Transition Pore* , 2000, The Journal of Biological Chemistry.

[106]  Y. Akao,et al.  Arsenic trioxide-induced apoptosis and its enhancement by buthionine sulfoximine in hepatocellular carcinoma cell lines. , 2002, Biochemical and biophysical research communications.

[107]  S. Lee,et al.  Apoptosis, bcl2 expression, and cell cycle analyses in nickel(II)-treated normal rat kidney cells. , 2001, Journal of Korean medical science.

[108]  Kazuo T. Suzuki,et al.  Mechanism of cadmium-induced cytotoxicity in rat hepatocytes: cadmium-induced active oxygen-related permeability changes of the plasma membrane , 1996 .

[109]  J. Bustamante,et al.  Early redox changes during rat thymocyte apoptosis. , 1997, Archives of biochemistry and biophysics.

[110]  P. Krammer.  CD95(APO-1/Fas)-mediated apoptosis: live and let die. , 1999, Advances in immunology.

[111]  Keunchil Park,et al.  Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. , 2003, Biochemical and biophysical research communications.

[112]  M. McAleer,et al.  Metallothionein protects against severe oxidative stress-induced apoptosis of human trophoblastic cells. , 2001, In vitro & molecular toxicology.

[113]  Xianglin Shi,et al.  The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. , 2000, American journal of physiology. Cell physiology.

[114]  R. González-Amaro,et al.  Effect of arsenic, cadmium and lead on the induction of apoptosis of normal human mononuclear cells , 2002, Clinical and experimental immunology.

[115]  Jen-kun Lin,et al.  Involvement of reactive oxygen species and caspase 3 activation in arsenite‐induced apoptosis , 1998, Journal of cellular physiology.

[116]  A. Sharifi,et al.  Investigation of acute lead poisoning on apoptosis in rat hippocampus in vivo , 2002, Neuroscience Letters.

[117]  A. Rabbani,et al.  Lead nitrate induced apoptosis in alveolar macrophages from rat lung. , 2000, Toxicology.

[118]  Y. Akao,et al.  Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. , 2002, Life sciences.

[119]  Brent R. Stockwell,et al.  An Induced Proximity Model for Caspase-8 Activation* , 1998, The Journal of Biological Chemistry.

[120]  J. Orenstein,et al.  Apoptosis is the mode of cell death caused by carcinogenic chromium. , 1994, Toxicology and applied pharmacology.

[121]  D. Menzel,et al.  Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis. , 1999, Biochemical and biophysical research communications.

[122]  P. Ho,et al.  Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines , 2001, Cancer Chemotherapy and Pharmacology.

[123]  Min Gao,et al.  Altered oxidative stress responses in nickel-resistant mammalian cells. , 1994, Cancer research.

[124]  N. Thornberry,et al.  Caspases: killer proteases. , 1997, Trends in biochemical sciences.

[125]  S. D'souza,et al.  Delayed Apoptosis Post-Cadmium Injury in Renal Proximal Tubule Epithelial Cells , 2002, American Journal of Nephrology.

[126]  C. Ong,et al.  Cadmium‐induced apoptosis and phenotypic changes in mouse thymocytes , 2001, Molecular and Cellular Biochemistry.

[127]  Jia-Ling Yang,et al.  Comparison of roles of three mitogen‐activated protein kinases induced by chromium(VI) and cadmium in non‐small‐cell lung carcinoma cells , 2001, Molecular and Cellular Biochemistry.

[128]  A. Bode,et al.  Apoptosis induction by arsenic: mechanisms of action and possible clinical applications for treating therapy-resistant cancers. , 2000, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[129]  A. Gavin,et al.  SIGNAL TRANSDUCTION:Cell Survival Demands Some Rsk , 1999 .

[130]  Weiya Ma,et al.  Requirement of Erk, but Not JNK, for Arsenite-induced Cell Transformation* , 1999, The Journal of Biological Chemistry.

[131]  L. Zon,et al.  Protein-Damaging Stresses Activate c-Jun N-Terminal Kinase via Inhibition of Its Dephosphorylation: a Novel Pathway Controlled by HSP72 , 1999, Molecular and Cellular Biology.

[132]  Yu-Jung Cheng,et al.  Enhancement of TNF-alpha expression does not trigger apoptosis upon exposure of glial cells to lead and lipopolysaccharide. , 2002, Toxicology.

[133]  M. Webber,et al.  Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis. , 2000, Toxicology and applied pharmacology.

[134]  G. Kroemer,et al.  Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. , 1999, Experimental cell research.

[135]  D. Green,et al.  Mechanisms of p53-dependent apoptosis. , 2001, Biochemical Society transactions.

[136]  Qing‐Li Zhao,et al.  Apoptosis Induced by Cadmium in Human Lymphoma U937 Cells through Ca2+-calpain and Caspase-Mitochondria- dependent Pathways* , 2000, The Journal of Biological Chemistry.