EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I-associated adult T-cell leukemia/lymphoma.
Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent pro-inflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo[1,2-a]quinoxalines, exhibits an important cytotoxic activity in vitro. HTLV-I-associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using potentially achievable concentrations of EAPB0203, we demonstrate inhibition of cell proliferation, G2/M cell- cycle arrest, and induction of apoptosis in HTLV-I-transformed and HTLV-I-negative malignant T cells and fresh ATL cells, whereas normal resting or activated T lymphocytes were resistant. EAPB0203 treatment significantly down-regulated the antiapoptotic proteins c-IAP-1 and Bcl-XL and resulted in a significant loss of mitochondrial membrane potential, cytoplasmic release of cytochrome c, and caspase-dependent apoptosis. Moreover, in HTLV-I-transformed cells only, EAPB0203 treatment stabilized p21 and p53 proteins but had no effect on NF-kappaB activation. These results support a potential therapeutic role for EAPB0203 in ATL and HTLV-I-negative T-cell lymphomas, either as a systemic or topical therapy for skin lesions.
Moarbess
Georges
G
Pharmacochimie et Biomolécules, Université Montpellier I, Faculté de Pharmacie, France.
El-Hajj
Hiba
H
Kfoury
Youmna
Y
El-Sabban
Marwan E
ME
Lepelletier
Yves
Y
Hermine
Olivier
O
Deleuze-Masquéfa
Carine
C
Bonnet
Pierre-Antoine
PA
Bazarbachi
Ali
A
D000634:Aminoquinolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D000077271:Imiquimod; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000634:Aminoquinolines; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C528810:EAPB0203; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011810:Quinoxalines; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D045304:Cytochromes c; D020169:Caspases; D000077271:Imiquimod