Apoptosis inducers in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by a typical defect in apoptosis and is still an incurable disease. Numerous apoptosis inducers have been described. These synthetic compounds and natural products (mainly derived from plants) display antileukemic properties in vitro and in vivo and some have even been tested in the clinic in CLL. They act through several different mechanisms. Most of them involve proteins of the Bcl-2 family, which are the key regulators in triggering the mitochondrial pathway of caspase-dependent apoptosis. Thus, the Mcl-1/Noxa axis appeared as a target. Here I overview natural and synthetic apoptosis inducers and their mechanisms of action in CLL cells. Opportunities for developing novel, apoptosis-based therapeutics are presented.

[1]  Mark W Lowdell,et al.  2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. , 2009, Blood.

[2]  E. Campo,et al.  Bendamustine Is Effective in p53-Deficient B-Cell Neoplasms and Requires Oxidative Stress and Caspase-Independent Signaling , 2008, Clinical Cancer Research.

[3]  G. Cohen,et al.  CDDO induces apoptosis via the intrinsic pathway in lymphoid cells , 2004, Leukemia.

[4]  S. Fulda.  Tumor resistance to apoptosis , 2009, International journal of cancer.

[5]  G. Russo,et al.  Quercetin induced apoptosis in association with death receptors and fludarabine in cells isolated from chronic lymphocytic leukaemia patients , 2010, British Journal of Cancer.

[6]  B. Bauvois,et al.  Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa. , 2011, International journal of oncology.

[7]  P. Fisher,et al.  Targeting the Bcl-2 family for cancer therapy , 2013, Expert opinion on therapeutic targets.

[8]  J. Gribben,et al.  Update on therapy of chronic lymphocytic leukemia. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  K. Guo,et al.  Xanthones from mangosteen extracts as natural chemopreventive agents: potential anticancer drugs. , 2011, Current molecular medicine.

[10]  U. Jaeger,et al.  Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia. , 2010, Blood.

[11]  A. Rosenwald,et al.  The microenvironment in mature B-cell malignancies: a target for new treatment strategies. , 2009, Blood.

[12]  J. Byrd,et al.  Phase II study of single‐agent bortezomib for the treatment of patients with fludarabine‐refractory B‐cell chronic lymphocytic leukemia , 2006, Cancer.

[13]  M. Woodle,et al.  In Vivo Application of RNA Interference: From Functional Genomics to Therapeutics , 2005, Advances in Genetics.

[14]  L. Lam,et al.  Souers AJ, Leverson JD, Boghaert ER et al.ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19:202-208 , 2013 .

[15]  A. Faussat,et al.  Apoptotic effects on B-cell chronic lymphocytic leukemia (B-CLL) cells of heterocyclic compounds isolated from Guttiferaes. , 2008, Leukemia research.

[16]  S. Bhaumik,et al.  The 26S proteasome complex: an attractive target for cancer therapy. , 2012, Biochimica et biophysica acta.

[17]  Derek A. West,et al.  The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. , 2009, Blood.

[18]  G. Russo,et al.  ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation. , 2013, Biochemical pharmacology.

[19]  W. Plunkett,et al.  Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. , 2009, Blood.

[20]  T. Chan,et al.  Recent advances on tea polyphenols. , 2012, Frontiers in bioscience.

[21]  M. Butterworth,et al.  Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells , 2010, Haematologica.

[22]  J. Kolb,et al.  Re-establishment of a normal apoptotic process as a therapeutic approach in B-CLL. , 2003, Current drug targets. Cardiovascular & haematological disorders.

[23]  Laurent Bélec,et al.  Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis , 2007, Proceedings of the National Academy of Sciences.

[24]  J. Pinilla-Ibarz,et al.  Treatment of relapsed or refractory chronic lymphocytic leukemia. , 2012, Cancer control : journal of the Moffitt Cancer Center.

[25]  M. Caligiuri,et al.  IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. , 2008, Blood.

[26]  A. Kater,et al.  Tipping the Noxa/Mcl-1 Balance Overcomes ABT-737 Resistance in Chronic Lymphocytic Leukemia , 2011, Clinical Cancer Research.

[27]  J. Byrd,et al.  Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia , 2009, British journal of haematology.

[28]  A. Eastman,et al.  Vinblastine Rapidly Induces NOXA and Acutely Sensitizes Primary Chronic Lymphocytic Leukemia Cells to ABT-737 , 2013, Molecular Cancer Therapeutics.

[29]  J. Gribben,et al.  5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  A. Strasser,et al.  Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim. , 2010, Blood.

[31]  P. Youinou,et al.  Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia , 2010, Journal of hematology & oncology.

[32]  G. Packham,et al.  Bodyguards and assassins: Bcl‐2 family proteins and apoptosis control in chronic lymphocytic leukaemia , 2005, Immunology.

[33]  Liang Xu,et al.  Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB , 2010, PloS one.

[34]  S. Korsmeyer,et al.  An inhibitor of Bcl-2 family proteins induces regression of solid tumours , 2005, Nature.

[35]  J. Philippé,et al.  Xanthohumol activates the proapoptotic arm of the unfolded protein response in chronic lymphocytic leukemia. , 2009, Anticancer research.

[36]  A. Faussat,et al.  4-arylcoumarin analogues of combretastatins stimulate apoptosis of leukemic cells from chronic lymphocytic leukemia patients. , 2008, Experimental hematology.

[37]  A. Eastman,et al.  Multiple BH3 Mimetics Antagonize Antiapoptotic MCL1 Protein by Inducing the Endoplasmic Reticulum Stress Response and Up-regulating BH3-only Protein NOXA* , 2011, The Journal of Biological Chemistry.

[38]  R. Mohammad,et al.  Analysis of resveratrol‐induced apoptosis in human B‐cell chronic leukaemia , 2002, British journal of haematology.

[39]  C. Scott,et al.  The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. , 2006, Cancer cell.

[40]  A. Faussat,et al.  Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia , 2006, Leukemia.

[41]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[42]  S. Bruno,et al.  N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity , 2012, Leukemia.

[43]  W. Plunkett,et al.  Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. , 2005, Blood.

[44]  Chun-ching Lin,et al.  Isoliquiritigenin induces apoptosis and cell cycle arrest through p53-dependent pathway in Hep G2 cells. , 2005, Life sciences.

[45]  B. Bauvois,et al.  Mechanistic insights into the antileukemic activity of hyperforin. , 2012, Current cancer drug targets.

[46]  J. Byrd,et al.  Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia. , 2013, Blood.

[47]  T. Kipps,et al.  AT-101, a small molecule Bcl-2 antagonist, in treatment naïve CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  V. Puduvalli,et al.  Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. , 2012, Blood.

[49]  Hao Xiong,et al.  Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  F. Mentz,et al.  Comparative Antiproliferative and Apoptotic Effects of Resveratrol, ϵ-viniferin and Vine-shots Derived Polyphenols (Vineatrols) on Chronic B Lymphocytic Leukemia Cells and Normal Human Lymphocytes , 2002, Leukemia & lymphoma.

[51]  E. Campo,et al.  Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM. , 2009, Blood.

[52]  H. Döhner,et al.  Experimental Therapeutics , Molecular Targets , and Chemical Biology A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia , 2009 .

[53]  M. Grever,et al.  Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. , 2003, Blood.

[54]  L. Pleyer,et al.  Molecular and cellular mechanisms of CLL: novel therapeutic approaches , 2009, Nature Reviews Clinical Oncology.

[55]  P. Colman,et al.  BCL-2 family antagonists for cancer therapy , 2008, Nature Reviews Drug Discovery.

[56]  A. Ballestrero,et al.  Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis. , 2005, Blood.

[57]  M. Grever,et al.  A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. , 2004, Blood.

[58]  J. Opferman,et al.  A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. , 2012, Chemistry & biology.

[59]  Xianglin Shi,et al.  Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo , 2011, Molecular Cancer Therapeutics.

[60]  C. Peschel,et al.  Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells , 2004, Leukemia.

[61]  Lisa S. Chen,et al.  Inflammation and survival pathways: chronic lymphocytic leukemia as a model system. , 2010, Biochemical pharmacology.

[62]  S. Baird,et al.  IAP-targeted therapies for cancer , 2008, Oncogene.

[63]  G. Cohen,et al.  Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells , 2008 .

[64]  Jeffrey A Jones,et al.  Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  L. Lam,et al.  ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets , 2013, Nature Medicine.

[66]  J. Nör,et al.  Small-molecule inhibitors reveal a new function for Bcl-2 as a proangiogenic signaling molecule. , 2011, Current topics in microbiology and immunology.

[67]  Di Chen,et al.  Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. , 2006, Cancer research.

[68]  J. Wang,et al.  ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia , 2011, Oncogene.

[69]  H. Kantarjian,et al.  Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia. , 2010, Blood.

[70]  Christian Billard,et al.  Flavones and polyphenols inhibit the NO pathway during apoptosis of leukemia B-cells. , 2004, Leukemia research.

[71]  L. Walensky,et al.  Direct and selective small-molecule activation of proapoptotic BAX. , 2012, Nature chemical biology.

[72]  T. Kipps,et al.  Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation , 2005, Leukemia.

[73]  J. Byrd,et al.  The Proteasome Inhibitor Carfilzomib Functions Independently of p53 to Induce Cytotoxicity and an Atypical NF-κB Response in Chronic Lymphocytic Leukemia Cells , 2013, Clinical Cancer Research.

[74]  A. Strasser,et al.  Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases , 2011, The EMBO journal.

[75]  G. Pons,et al.  Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells , 2007, Leukemia.

[76]  T. Shanafelt,et al.  VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. , 2004, Blood.

[77]  D. Fennell,et al.  BCL-2 family regulation by the 20S proteasome inhibitor bortezomib , 2007, Oncogene.

[78]  E. González-Barca,et al.  AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. , 2010, Blood.

[79]  Thomas S. Lin,et al.  Flavopiridol in chronic lymphocytic leukemia: a concise review. , 2009, Clinical lymphoma & myeloma.

[80]  Deborah A. Bowen,et al.  Phase 2 trial of daily, oral polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia , 2013, Cancer.

[81]  M. Grever,et al.  Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. , 1998, Blood.

[82]  S. Shankar,et al.  Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. , 2007, Frontiers in bioscience : a journal and virtual library.

[83]  C. Billard.  Development of Noxa-like BH3 Mimetics for Apoptosis-Based Therapeutic Strategy in Chronic Lymphocytic Leukemia , 2012, Molecular Cancer Research.

[84]  G. Gores,et al.  A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells. , 2010, Cancer research.

[85]  S. Aiyar,et al.  TMS, a chemically modified herbal derivative of Resveratrol, induces cell death by targeting Bax , 2010, Breast Cancer Research and Treatment.

[86]  Michael T. Certo,et al.  Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. , 2007, The Journal of clinical investigation.

[87]  V. Gandhi,et al.  Bax and Bak are required for apogossypolone, a BH3-mimetic, induced apoptosis in chronic lymphocytic leukemia cells , 2013, Leukemia & lymphoma.

[88]  M. Caligiuri,et al.  Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity , 2007, Clinical Cancer Research.

[89]  Di Chen,et al.  Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. , 2005, Biochemical pharmacology.

[90]  J. Kolb,et al.  Noxa upregulation is associated with apoptosis of chronic lymphocytic leukemia cells induced by hyperforin but not flavopiridol , 2009, Leukemia.

[91]  G M Cohen,et al.  Different forms of cell death induced by putative BCL2 inhibitors , 2009, Cell Death and Differentiation.

[92]  M. Keating,et al.  Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. , 2008, Blood.

[93]  G. Berchem,et al.  The Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase Activation Cascade , 2010, Molecular Cancer Therapeutics.

[94]  D. Claxton,et al.  Obatoclax mesylate: pharmacology and potential for therapy of hematological neoplasms , 2012, Expert opinion on investigational drugs.

[95]  T. Efferth,et al.  Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1 , 2011, Cell Death and Disease.

[96]  J. Grandis,et al.  The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4 , 2012, Autophagy.

[97]  Qiaojun He,et al.  MZ3 can induce G2/M-phase arrest and apoptosis in human leukemia cells , 2008, Journal of Cancer Research and Clinical Oncology.

[98]  G. Pons,et al.  Aspirin induces apoptosis in human leukemia cells independently of NF-κB and MAPKs through alteration of the Mcl-1/Noxa balance , 2010, Apoptosis.

[99]  K. J. Henley,et al.  Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor , 2012, Cell Death and Disease.

[100]  Jeffrey A Jones,et al.  The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells , 2012, Leukemia.

[101]  B. Bauvois,et al.  p70S6 kinase is a target of the novel proteasome inhibitor 3,3'-diamino-4'-methoxyflavone during apoptosis in human myeloid tumor cells. , 2013, Biochimica et biophysica acta.

[102]  V. Gandhi,et al.  AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. , 2009, Blood.

[103]  Evripidis Gavathiotis,et al.  A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. , 2012, The Journal of clinical investigation.

[104]  Lei Guo,et al.  Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. , 2011, Blood.

[105]  C. Billard.  Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia , 2012, Leukemia.

[106]  G. Cohen,et al.  Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa , 2007, Leukemia.

[107]  Norma I Rodríguez-Malavé,et al.  MicroRNAs in B cell development and malignancy , 2012, Journal of Hematology & Oncology.

[108]  R. Oostendorp,et al.  Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1 , 2011, Leukemia.

[109]  T. Shanafelt,et al.  Curcumin Inhibits Prosurvival Pathways in Chronic Lymphocytic Leukemia B Cells and May Overcome Their Stromal Protection in Combination with EGCG , 2009, Clinical Cancer Research.

[110]  P. Hersey,et al.  Involvement of BH3-only proapoptotic proteins in mitochondrial-dependent Phenoxodiol-induced apoptosis of human melanoma cells , 2006, Anti-cancer drugs.

[111]  M. Templin,et al.  Delivery and biodistribution of siRNA for cancer therapy: challenges and future prospects. , 2012, Therapeutic delivery.

[112]  S. Stilgenbauer.  Chemoimmunotherapy in chronic lymphocytic leukemia. , 2010, Clinical advances in hematology & oncology : H&O.

[113]  A. Roberts,et al.  Overcoming blocks in apoptosis with BH3-mimetic therapy in haematological malignancies , 2011, Pathology.

[114]  T. Stankovic,et al.  Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. , 2008, Blood.

[115]  S. Parodi,et al.  Apoptosis of B-cell chronic lymphocytic leukemia cells induced by a novel BH3 peptidomimetic , 2009, Cancer biology & therapy.

[116]  Thomas S. Lin,et al.  Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab. , 2009, Blood.

[117]  A. Hunter,et al.  Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an ∼700 kDa Apaf-1 containing apoptosome complex , 2001, Leukemia.

[118]  John Calvin Reed.  Apoptosis-targeted therapies for cancer. , 2003, Cancer cell.