Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine

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Abstract

Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 μM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill.

What's new?

Acid ceramidase, one of the key enzymes in sphingolipid metabolism, has been identified as a promising target for cancer therapy. Using a head and neck cancer mouse model, here the authors examine the effectiveness of acid ceramidase inhibitor LCL521 as adjuvant to photodynamic therapy (PDT). They show that targeting acid ceramidase can be successfully exploited in combined treatments with PDT or PDT-generated vaccines. LCL521 treatment enhances direct lethal effects initiated by PDT-induced oxidative stress responses in vitro. In vivo, the hindering effects of major immunoregulatory populations following PDT of tumors or related vaccine protocols can be restrained by LCL521 treatment.

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