Ceramide promotes the death of human cervical tumor cells in the absence of biochemical and morphological markers of apoptosis.
C8-ceramide, a synthetic cell-permeable analog of endogenous ceramides, interfered with cell proliferation, and was cytotoxic to papilloma virus-containing human cervix carcinoma cells, CALO, INBL, and HeLa, that match two clinical stages of tumor progression. C8-ceramide (3 microM) markedly reduced the tumor cell number after 48 h of treatment, an effect that endured even after the removal of C8-ceramide. The carcinoma cells showed morphologic changes, characteristic of necrosis and released lactate dehydrogenase (LDH). A biologically inactive analog C8-dihydro-ceramide had no effect on cell viability in any of the cell lines tested. Seventy-two hours after C8-ceramide treatment none of the biochemical and morphological markers characteristic of apoptosis: (a) nuclear chromatin condensation, (b) DNA fragmentation, (c) proteolysis of the caspase-3 substrate poly-(ADP-ribose)-polymerase (PARP), and (d) appearance of phosphatidylserine on the external cell membrane, were observed. C8-ceramide had no effect on human cervix fibroblasts and induced a mild reduction (30%) in the proliferation of normal human cervix epithelia and HeLa cells (IV-B metastatic stage). The cytotoxicity of C8-ceramide was restricted to CALO (early II-B) and INBL (IV-A non-metastatic) carcinoma cells. The possible application of ceramide in the treatment of early stages of cervical cancer is discussed.
López-Marure
Rebeca
R
Departamento de Biología Celular, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1, Colonia Sección 16, Tlalpan, C.P. 14080, Mexico DF, Mexico. rmarure@hotmail.com
Gutiérrez
Gisela
G
Mendoza
Criselda
C
Ventura
José Luis
JL
Sánchez
Luis
L
Reyes Maldonado
Elba
E
Zentella
Alejandro
A
Montaño
Luis Felipe
LF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D002584:Cervix Uteri / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D015415:Biomarkers; D002518:Ceramides; D007770:L-Lactate Dehydrogenase