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.