МICELLAR'CURCUMIN'SUBSTANTIALLY'INCREASES'THE'ANTINEOPLASTIC'AND'
ANTIMICROBIAL'EFFICACY'OF'ЕRUFOSINE'AGAINST'TWIST1'POSITIVE'
CUTANEOUS'TICELL'LYMPHOMA'CELLS'AND'GRAMIPOSITIVE'PATHOGENIC'
POSTER'6'
BACTERIA'
'
Maya! M! Zaharieva1,! Antonios! Trochopoulos2,! Yana! Illieva1,! Alexander! Kroumov1,! Lyudmila!
Dimitrova1,! Stanislav! Philipov3,! Ivanka! PenchevaJEl! Tibi4,! Krassimira! Yoncheva5,! Martin! R.! Berger6,!
Hristo!Najdenski7!and!Spiro!Konstantinov2!
!
(1)The! Stephan! Angeloff! Institute! of! Microbiology,! Bulgarian! Academy! of! Sciences,! Sofia,! Bulgaria,!
(2)Department! of! Pharmacology,! Pharmacotherapy! and! Toxicology,! Faculty! of! Pharmacy,! Medical!
University!of!Sofia,!2!Dunav!Str,!1000,!Sofia,!Bulgaria,!(3)Chair!Human!Anatomy,!Histology,!General!
and!Clinical!Pathology!and!Forensic!Medicine,!Faculty!of!Medicine,!University!Hospital!Lozenetz,!Sofia!
University!“St.!Kliment!Ohridski”,!Sofia,!Bulgaria,!(4)Department!of!Pharmaceutical!Chemistry,!Faculty!
of! Pharmacy,! Medical! University! of! Sofia,! 2! Dunav! Str,! 1000,! Sofia,! Bulgaria,! (5)Department! of!
Pharmaceutical!Technology!and!Biopharmaceutics,!Faculty!of!Pharmacy,!Medical!University!of!Sofia,!
2!Dunav!Str,!1000,!Sofia,!Bulgaria,!(6)Toxicology!and!Chemotherapy!Unit,!German!Cancer!Research!
Center,! 69120,! Heidelberg,! Germany,! (7)Institute! of! Microbiology,! Bulgarian! Academy! of! Sciences,!
Sofia,!Bulgaria!
!
Objectives:!The!orphan!disease!cutaneous!TJcell!lymphoma!(CTCL)!primarily!affects!the!skin!
by! clonal! accumulation! of! CD4+CD45RO+! helper/memory! neoplastic! TJlymphocytes.! CTCL!
progression!and!dissemination!are!related!to!expression!of!the!transcription!factor!TWIST1.!
Concomitant! bacterial! infections! due! to! impaired! skin! barrier! and! immune! deficiency!
increase!the!morbidity!and!mortality!rates.!CTCL!therapy!is!often!empiric!and!not!based!on!
specific! molecular! alterations.! Therefore,! development! of! new! treatment! modalities! is!
needed.!
Methods:!The!cell!lines!HuT78,!HH!and!MJ!were!used!as!in!vitro!models!for!CTCL.!Median!
inhibitory!concentrations!were!determined!following!Annex!C!of!ISO!10993J5:2009.!Protein!
expression!was!evaluated!by!immunoblot!assay!using!specific!antibodies!against!TWIST1!and!
PKB/Akt.! NFκBJp65! activity! was! measured! by! ELISA! test.! The! metabolic! activity! of!
prokaryotic! and! eukaryotic! cells! was! calculated! with! the! mathematical! software! MAPLE.!
Minimal!bactericidal!and!inhibitory!concentrations,!metabolic!activity!and!biofilm!reduction!
were! determined! by! ISO! 20776J1:2006(E),! CFU! enumeration,! MTT! assay! and! the! test! of!
Stepanovic1,! respectively.! The! tested! bacterial! strains! included! methicillin! sensitive! and!
resistant!Staphylococcus!aureus!and!Streptococcus!pyogenes.!
Results:!In! the! current! study,! we! showed! that! the! antilymphoma! potential! of! erufosine!
depends!on!the!TWIST1!expression!level,!but!combinations!with!micellar!curcumin!(MCRM)!
included! in! methoxy! poly(ethylene! glycol)JblockJpoly(εJcaprolactone)! copolymer! carrier!
overcome! this! relative! resistance.! MCRM! was! characterized! by! low! zetaJpotential,! slow!
release! of! curcumin! and! fast! cell! membrane! penetration.! The! median! inhibitory!
concentrations! of! erufosine! were! compared! in! CTCL! cell! lines! by! the! MTTJdye! reduction!
assay.!Combinations!of!Erufosine!with!MCRM!at!a!ratio!of!1:4!were!found!to!be!synergistic.!
Combination! effects! were! processed! to! draw! respective! isobolograms! using! the! MAPLE!
software.!The!synergistic!combination!inhibited!the!expression!of!TWIST1!and!protein!kinase!
B/Akt!and!induced!autophagy!as!proven!by!western!blotting!for!LC3A/B.!Noteworthy,!NFκB!
activation!was!reduced!as!measured!with!specific!ELISA.!Cell!death!ELISA,!caspaseJ3!activity,!
glutathione!and!CFU!assays!revealed!induction!of!apoptosis,!altered!glutathione!levels!and!
SCIENTIFIC PROGRAMME
SESSION I
HODGKIN’S DISEASE
DEBATE I
IS THERE STILL A ROLE
FOR COMBINED MODALITY
THERAPY FOR EARLY
STAGE CHL?
SESSION II
T-CELL LYMPHOMA
ROUNDTABLE I
FUTURE DIRECTIONS IN
T-CELL LYMPHOMA
SESSION III
FOLLICULAR LYMPHOMA
DEBATE II
CAN WE AVOID
CHEMOTHERAPY IN
THE MANAGEMENT OF
FOLLICULAR LYMPHOMA?
SESSION IV
RARE LYMPHOMAS –
MARGINAL ZONE
LYMPHOMA AND
WALDENSTRÖM M
ACROGLOBULINEMIA
ROUNDTABLE II – WHERE
TO GO IN RARE B-CELL
LYMPHOMAS
SESSION V
MANTLE CELL LYMPHOMA
SESSION VI
DIFFUSE LARGE B-CELL
LYMPHOMA
DEBATE III
DO WE STILL NEED ASCT
IN MCL?
SESSION VII
NOVEL THER APEUTIC
CONCEPTS IN B-CELL
LYMPHOMAS
SELECTED ABSTRACTS
FOR AN ORAL
PRESENTATION
SELECTED ABSTRACTS
FOR A POSTER
PRESENTATION
DISCLOSURES