Photodynamic therapy (
PDT) is known to alter the expression of various genes in treated cells. This prompted us to examine the activity of genes encoding two important
enzymes in
sphingolipid (SL) metabolism,
dihydroceramide desaturase (DES) and
sphingosine kinase (SPHK), in mouse SCCVII
tumor cells treated by
PDT using either the
porphyrin-based
photosensitizer Photofrin or
silicon phthalocyanine Pc4. The results revealed that
PDT induced an upregulation in the expression of two major
isoforms of both genes (DES1 and DES2 as well as SPHK1 and SPHK2). While the changes were generally moderate (2-3-fold gains), the increase in DES2 expression was more pronounced and it was much greater with
Photofrin-
PDT than with Pc4-PDT (over 23-fold vs. less than 5-fold). Combining either
Photofrin-
PDT or Pc4-PDT with the cationic
C16-ceramide LCL30 (20mg/kg i.p.) for treatment of subcutaneously growing SCCVII
tumors rendered important differences in the
therapy outcome.
Photofrin-
PDT, used at a dose that attained good initial response but no
tumor cures, produced 50% cures when combined with a single
LCL30 treatment. In contrast, the same
LCL30 treatment combined with Pc4-PDT had no significant effect on
tumor response. The optimal timing of
LCL30 injection was immediately after
Photofrin-
PDT. The therapeutic benefit was lost when
LCL30 was given in two 20mg/kg
injections encompassing intervals before and after
PDT. LCL85, the cationic B13
ceramide analogue and SL-modulating agent, also increased cure rates of
Photofrin-
PDT treated
tumors, but the therapeutic benefit was less pronounced than with
LCL30. These results with
LCL30 and LCL85, and our previous findings for LCL29 (another SL analogue), assert the potential of SLs for use as adjuvants to augment the efficacy of
PDT-mediated
tumor destruction.