Micellar Curcumin Substantially Increases the Antineoplastic Activity of the Alkylphosphocholine Erufosine against TWIST1 Positive Cutaneous T Cell Lymphoma Cell Lines

Cutaneous T-cell lymphoma (CTCL) is a rare form of cancer with local as well as systemic manifestations. Concomitant bacterial infections increase morbidity and mortality rates due to impaired skin barrier and immune deficiency. In the current study, we demonstrated that the in vitro anti-lymphoma potential of erufosine is diminished by TWIST1 expression and micellar curcumin substantially increases its antineoplastic activity. Pharmacokinetic analysis showed that the micellar curcumin (MCRM) used in our study was characterized by low zeta potential, slow release of curcumin, and fast cell membrane penetration. The combination ratio 1:4 [erufosine:MCRM] achieved strong synergism by inhibiting cell proliferation and clonogenicity. The combined antiproliferative effects were calculated using the symbolic mathematical software MAPLE 15. The synergistic combination strongly decreased the expression of TWIST1 and protein kinase B/Akt as proven by western blotting. Significant reductions in NF-κB activation, induction of apoptosis, and altered glutathione levels were demonstrated by corresponding assays. In addition, the synergistic combination enhanced the anti-staphylococcal activity and prevented biofilm formation, as shown by crystal violet staining. Taken together, the above results show that the development of nanotechnological treatment modalities for CTCL, based on rational drug combinations exhibiting parallel antineoplastic and antibacterial effects, may prove efficacious.

[1]  M. Čuperlović-Culf,et al.  Role of Glutathione in Cancer: From Mechanisms to Therapies , 2020, Biomolecules.

[2]  M. Berger,et al.  Antineoplastic effect of a novel nanosized curcumin on cutaneous T cell lymphoma , 2020, Oncology letters.

[3]  E. Guenova,et al.  Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020 , 2020, International Archives of Allergy and Immunology.

[4]  P. Wolf,et al.  Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time , 2020, Transfusion Medicine and Hemotherapy.

[5]  S. Rozati,et al.  Update on Biology of Cutaneous T-Cell Lymphoma , 2020, Frontiers in Oncology.

[6]  R. Knobler,et al.  Recent advances in understanding and managing cutaneous T-cell lymphomas , 2020, F1000Research.

[7]  K. Yoncheva,et al.  Micellar curcumin improves the antibacterial activity of the alkylphosphocholines erufosine and miltefosine against pathogenic Staphyloccocus aureus strains , 2019, Biotechnology & Biotechnological Equipment.

[8]  M. Berger,et al.  Alkylphospholipids are Signal Transduction Modulators with Potential for Anticancer Therapy. , 2019, Anti-cancer agents in medicinal chemistry.

[9]  M. Simon,et al.  Glutathione metabolism in cancer progression and treatment resistance , 2018, The Journal of cell biology.

[10]  A. Kroumov,et al.  New Insights in Routine Procedure for Mathematical Evaluation of in vitro Cytotoxicity Data from Cancer Cell Lines , 2018, International Journal Bioautomation.

[11]  E. Conde-Montero,et al.  Epidemiological and clinical features of patients diagnosed with cutaneous T‐cell lymphomas in a Spanish tertiary care hospital , 2017, Journal of the European Academy of Dermatology and Venereology : JEADV.

[12]  Z. Chen,et al.  Multiple biological functions of Twist1 in various cancers , 2017, Oncotarget.

[13]  Thiago Caon,et al.  Lipid- and Polymer-Based Nanostructures for Cutaneous Delivery of Curcumin , 2017, AAPS PharmSciTech.

[14]  K. thestrup-pedersen.  Cutaneous T‐Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair , 2016, Journal of the European Academy of Dermatology and Venereology : JEADV.

[15]  B. Smoller,et al.  An overview of cutaneous T cell lymphomas , 2016, F1000Research.

[16]  H. Wong.  STAT Assays with a TWIST: Differentiating Sézary Syndrome from Erythrodermic Inflammatory Dermatitis. , 2016, The Journal of investigative dermatology.

[17]  W. Damsky,et al.  Genetics of Cutaneous T Cell Lymphoma: From Bench to Bedside , 2016, Current Treatment Options in Oncology.

[18]  M. Felcht,et al.  Sézary syndrome: old enigmas, new targets , 2016, Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG.

[19]  R. Wilcox,et al.  Cutaneous T‐cell lymphoma: 2016 update on diagnosis, risk‐stratification, and management , 2016, American journal of hematology.

[20]  S. Pileri,et al.  Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Cutaneous T-cell lymphomas. , 2016, Critical reviews in oncology/hematology.

[21]  Y. Kalia,et al.  Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle. , 2015, Nanoscale.

[22]  M. Duvic.  Histone Deacetylase Inhibitors for Cutaneous T-Cell Lymphoma. , 2015, Dermatologic clinics.

[23]  J. Zic.  Extracorporeal Photopheresis in the Treatment of Mycosis Fungoides and Sézary Syndrome. , 2015, Dermatologic clinics.

[24]  B. Poligone,et al.  Other Chemotherapeutic Agents in Cutaneous T-Cell Lymphoma. , 2015, Dermatologic clinics.

[25]  A. Rook,et al.  The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma. , 2015, Dermatologic clinics.

[26]  B. Aggarwal,et al.  Curcumin, a component of golden spice: from bedside to bench and back. , 2014, Biotechnology advances.

[27]  Y. Kalia,et al.  Polymeric micelle nanocarriers for the cutaneous delivery of tacrolimus: a targeted approach for the treatment of psoriasis. , 2014, Molecular pharmaceutics.

[28]  M. Berger,et al.  Reduced Expression of the Retinoblastoma Protein Shows That the Related Signaling Pathway Is Essential for Mediating the Antineoplastic Activity of Erufosine , 2014, PloS one.

[29]  M. Aumailley,et al.  The membrane-targeted alkylphosphocholine erufosine interferes with survival signals from the extracellular matrix. , 2014, Anti-cancer agents in medicinal chemistry.

[30]  M. Berger,et al.  Antineoplastic potential of curcumin (cooperative study in Bulgaria and Germany) , 2014, Phytochemistry Reviews.

[31]  A. Puisieux,et al.  The emerging role of Twist proteins in hematopoietic cells and hematological malignancies , 2014, Blood cancer journal.

[32]  K. Kerl,et al.  Cutaneous Lymphomas: An Update. Part 1 T-Cell and Natural Killer/T-Cell Lymphomas and Related Conditions , 2014, The American Journal of dermatopathology.

[33]  M. Berger,et al.  Alkylphosphocholines and curcumin induce programmed cell death in cutaneous T-cell lymphoma cell lines. , 2014, Leukemia research.

[34]  Qinjie Wu,et al.  A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing. , 2013, Biomaterials.

[35]  C. Geisler,et al.  Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma , 2013, Toxins.

[36]  Junjiang Fu,et al.  Twist: a molecular target in cancer therapeutics , 2013, Tumor Biology.

[37]  C. Glackin,et al.  TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production , 2012, BMC Biology.

[38]  M. Berger,et al.  Erufosine suppresses breast cancer in vitro and in vivo for its activity on PI3K, c-Raf and Akt proteins , 2012, Journal of Cancer Research and Clinical Oncology.

[39]  Satya N. Das,et al.  Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. , 2012, Cancer letters.

[40]  S. Majumdar,et al.  Oxidative Stress Induced by Curcumin Promotes the Death of Cutaneous T-cell Lymphoma (HuT-78) by Disrupting the Function of Several Molecular Targets , 2012, Molecular Cancer Therapeutics.

[41]  M. Goswami,et al.  Increased Twist expression in advanced stage of mycosis fungoides and Sézary syndrome , 2012, Journal of cutaneous pathology.

[42]  B. Aggarwal,et al.  Discovery of curcumin, a component of golden spice, and its miraculous biological activities , 2012, Clinical and experimental pharmacology & physiology.

[43]  C. Rüegg,et al.  Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes. , 2012, Cancer Discovery.

[44]  Z. Qian,et al.  Biodegradable self-assembled MPEG-PCL micelles for hydrophobic oridonin delivery in vitro. , 2012, Journal of biomedical nanotechnology.

[45]  B. Teicher,et al.  Erufosine, an alkylphosphocholine, with differential toxicity to human cancer cells and bone marrow cells , 2011, Cancer Chemotherapy and Pharmacology.

[46]  B. Chazotte.  Labeling nuclear DNA with hoechst 33342. , 2011, Cold Spring Harbor protocols.

[47]  C. Belka,et al.  The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation , 2010, Radiation oncology.

[48]  M. Hallek,et al.  Erufosine, a novel alkylphosphocholine, induces apoptosis in CLL through a caspase-dependent pathway. , 2010, Leukemia research.

[49]  B. Aggarwal,et al.  Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients' PBMCs: potential role for STAT-3 and NF-kappaB signaling. , 2010, The Journal of investigative dermatology.

[50]  J. McCubrey,et al.  Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms , 2010, Leukemia.

[51]  M. Berger,et al.  Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity , 2010, Cancer Chemotherapy and Pharmacology.

[52]  M. Berger,et al.  Erucylphospho‐N,N,N‐trimethylpropylammonium Shows Substantial Cytotoxicity in Multiple Myeloma Cells , 2009, Annals of the New York Academy of Sciences.

[53]  B. Aggarwal,et al.  Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. , 2009, Trends in pharmacological sciences.

[54]  K. Rathinasamy,et al.  Quantitative cellular uptake, localization and cytotoxicity of curcumin in normal and tumor cells. , 2008, Biochimica et biophysica acta.

[55]  K. Sainis,et al.  Delayed activation of PKCδ and NFκB and higher radioprotection in splenic lymphocytes by copper (II)–Curcumin (1:1) complex as compared to curcumin , 2007 .

[56]  Robert A Newman,et al.  Bioavailability of curcumin: problems and promises. , 2007, Molecular pharmaceutics.

[57]  W. Hiddemann,et al.  Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs , 2007, Cancer Chemotherapy and Pharmacology.

[58]  T. Sorrell,et al.  Synthesis, antifungal and antimicrobial activity of alkylphospholipids. , 2007, Bioorganic & medicinal chemistry.

[59]  S. Stepanović,et al.  Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci , 2007, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[60]  M. Berger,et al.  Erufosine: a membrane targeting antineoplastic agent with signal transduction modulating effects. , 2007, Annals of the New York Academy of Sciences.

[61]  L. Thomas,et al.  A phase II trial of miltefosine in patients with cutaneous T-cell lymphoma. , 2006, Bulletin du cancer.

[62]  C. Unger,et al.  Metabolism of ether phospholipids and analogs in neoplastic cells , 1987, Lipids.

[63]  B. Aggarwal,et al.  Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. , 2005, Biochemical pharmacology.

[64]  M. Diederich,et al.  Chemopreventive and therapeutic effects of curcumin. , 2005, Cancer letters.

[65]  A. Khar,et al.  Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. , 2004, Molecular cancer therapeutics.

[66]  R. Willemze,et al.  Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sézary Syndrome Identified by Gene Expression Analysis , 2004, Cancer Research.

[67]  H. Bartelink,et al.  Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase–Akt/PKB survival pathway , 2003, Anti-cancer drugs.

[68]  B. Aggarwal,et al.  Anticancer potential of curcumin: preclinical and clinical studies. , 2003, Anticancer research.

[69]  M. Berger,et al.  Combination effects of alkylphosphocholines and gemcitabine in malignant and normal hematopoietic cells. , 2002, Cancer letters.

[70]  D. Haase,et al.  Effects of hexadecylphosphocholine on thrombocytopoiesis. , 2001, European journal of cancer.

[71]  M. Berger,et al.  BCR‐ABL influences the antileukaemic efficacy of alkylphosphocholines , 1999, British journal of haematology.

[72]  A. Benner,et al.  Alkylphosphocholines: Effects on human leukemic cell lines and normal bone marrow cells , 1998, International journal of cancer.

[73]  H. Eibl,et al.  Erucylphosphocholine is the prototype of i. v. injectable alkylphosphocholines. , 1998 .

[74]  H. Eibl,et al.  Medical Application of Synthetic Phospholipids as Liposomes and Drugs , 1995 .

[75]  J. Verweij,et al.  Increases in leucocyte and platelet counts induced by the alkyl phospholipid hexadecylphosphocholine. , 1994, European journal of cancer.

[76]  R. Dummer,et al.  Topical administration of hexadecylphosphocholine in patients with cutaneous lymphomas: results of a phase I/II study. , 1993, Journal of the American Academy of Dermatology.

[77]  E. Vonderheid,et al.  Infections complicating mycosis fungoides and Sézary syndrome. , 1992, JAMA.

[78]  C. Unger,et al.  Alkylphosphocholines : new drugs in cancer therapy , 1992 .

[79]  J. Becker,et al.  Topical application of hexadecylphosphocholine in patients with cutaneous lymphomas. , 1992, Progress in experimental tumor research.

[80]  Haralampos J. Milionis,et al.  Cutaneous T-cell lymphoma. , 2005, The Journal of dermatologic surgery and oncology.

[81]  J. Sedlák,et al.  Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. , 1968, Analytical biochemistry.