Increased tumour dihydroceramide production after Photofrin-PDT alone and improved tumour response after the combination with the ceramide analogue LCL29. Evidence from mouse squamous cell carcinomas

Abstract

Photodynamic therapy (PDT) has been proven effective for treatment of several types of cancer. Photodynamic therapy alone, however, attains limited cures with some tumours and there is need for its improved efficacy in such cases. Sphingolipid (SL) analogues can promote tumour response in combination with anticancer drugs. In this study, we used mouse SCCVII squamous cell carcinoma tumours to determine the impact of Photofrin-PDT on the in vivo SL profile and the effect of LCL29, a C6-pyridinium ceramide, on PDT tumour response. Following PDT, the levels of dihydroceramides (DHceramides), in particular C20-DHceramide, were elevated in tumours. Similarly, increases in DHceramides, in addition to C20:1-ceramide, were found in PDT-treated SCCVII cells. These findings indicate the importance of the de novo ceramide pathway in Photofrin-PDT response not only in cells but also in vivo. Notably, co-exposure of SCCVII tumours to Photofrin-PDT and LCL29 led to enhanced tumour response compared with PDT alone. Thus, we show for the first time that Photofrin-PDT has a distinct signature effect on the SL profile in vitro and in vivo, and that the combined treatment advances PDT therapeutic gain, implying translational significance of the combination.

Enhanced tumor cures after Foscan photodynamic therapy combined with the ceramide analog LCL29. Evidence from mouse squamous cell carcinomas for sphingolipids as biomarkers of treatment response

“…1B relative to the de novo ceramide pathway. Others (20–25) and we (19,26–30) have shown the involvement of the de novo ceramide pathway in response to anticancer therapeutics, including PDT, in vitro and in vivo . Foscan, a photosensitizer more potent than Photofrin (31), and clinically proven effective for PDT of head and neck cancers (32), was chosen for these investigations.…”

“…Using LCL29 (11,18), in combination with Photofrin-PDT, we have shown moderately improved in vivo response of mouse SCCVII squamous carcinomas (19). However, the long-term effect of the combination PDT + LCL29 is unknown.…”

Sphingolipids in cancer

“…Moreover, SMase activation enhanced the killing effects of ionizing radiation in vitro and in vivo [90], and increasing endogenous ceramide levels in radioresistant HNSCC cell lines induced apoptosis by restoring the death signal transduction pathway, which had been ineffective following irradiation owing to a lack of ceramide generation [91]. Recently, it was demonstrated that ceramide analog LCL29 enhanced tumor response to photofrin-photodynamic therapy [92].…”

Bioactive Sphingolipids in Neuroblastoma

“…They had some inhibition at higher concentrations, supporting the fact that both agents may act indirectly on the enzyme (unpublished observations). Additionally, photodynamic therapy (Separovic et al, 2009), -tocopherol , and XM462 (Munoz-Olaya et al, 2008) may function as indirect inhibitors of dihydroceramide desaturase by modulating the redox status of the cells as in case of hydrogen peroxide.…”