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

Abstract

To improve anticancer therapeutic success of photodynamic therapy (PDT), combination treatments represent a viable strategy. Sphingolipid analogs combined with anticancer drugs can enhance tumor response. We have shown that LCL29, a C6-pyridinium ceramide, promotes therapeutic efficacy of Photofrin-PDT in mouse SCCVII squamous cell carcinoma tumors. The long-term effect of the combination PDT + LCL29 is unknown. In this study we used the same model to test the long-term curative potential of Foscan-PDT + LCL29. We show that treatment of SCCVII tumors with the combination led to enhanced long-term tumor cure compared to PDT alone. LCL29 itself did not prevent tumor growth. All treatments triggered early increases in tumor-associated C16-ceramide, C18-ceramide, dihydrosphingosine, and global levels of dihydroceramides. PDT-evoked increases in tumor-associated sphingosine-1-phosphate and dihydrosphingosine-1-phosphate remained elevated or were attenuated after the combination, respectively; in contrast, LCL29 had no effect on these two sphingolipids. Our data demonstrate that adjuvant LCL29 improves PDT long-term therapeutic efficacy, implying translational potential of the combination. Furthermore, our findings indicate that changes in the sphingolipid profile might serve as predictive biomarkers of tumor response to treatments.

C6-pyridinium ceramide sensitizes SCC17B human head and neck squamous cell carcinoma cells to photodynamic therapy

“…Combining PDT with LCL29 is a novel approach, as there have been no reports of this combination, apart from our in vivo studies [11, 12]. The present study shows that enhanced, FB-sensitive mitochondrial ceramide accumulation correlates with enhanced mitochondrial apoptosis and cell killing after combining PDT and LCL29.…”

“…1, panel A) [7], has been shown to act as an effective anticancer agent, alone or in combination with chemotherapy [5, 6, 9, 10]. We have shown in a syngeneic murine model of head and neck squamous cancer cell carcinoma (HNSCC) that combining PDT with LCL29 augments tumor-associated ceramide accumulation and apoptosis, as well as that the combination improves tumor response to PDT [11–13]. A better understanding of the mechanisms of improved tumor response after the combination is warranted, in order to exploit them to enhance cancer cell killing.…”

Cationic ceramides and analogues, LCL30 and LCL85, as adjuvants to photodynamic therapy of tumors

“…We have investigated the efficacy of one such agent, C6-ceramide analogue LCL29, as adjuvant to PDT. Our results show that cure rates of PDT-treated mouse squamous cell carcinomas SCCVII can be significantly increased by adjoined treatment with a single dose of LCL29 [11]. Further investigation revealed that the combined LCL29 treatment strongly amplified apoptosis in cancer cells of PDT-treated tumors [14].…”

“…ceramide, sphingosine and sphingosine-1-phosphate) are critical mediators of cellular stress responses and have prominent roles in cell apoptosis, autophagy, as well as immune cell functions [6-8]. Our earlier research has shown that SLs are important participants in response to PDT at both cellular and tumor levels [9-11]. Similar to chemotherapy and some other types of cancer therapy, PDT has a distinct signature effect on the SL profile owing in particular to induction of the de novo ceramide biosynthesis [11,12].…”

“…Our earlier research has shown that SLs are important participants in response to PDT at both cellular and tumor levels [9-11]. Similar to chemotherapy and some other types of cancer therapy, PDT has a distinct signature effect on the SL profile owing in particular to induction of the de novo ceramide biosynthesis [11,12]. De novo ceramide appears to be involved in the initiation of apoptosis of cancer cells after PDT [13,14].…”