Topical GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis

Abstract

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma (cSCC). There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cSCCs. We recently showed that GZ17-6.02, an anti-cancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. The present study evaluated the efficacy of a novel topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to ultraviolet irradiation. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (p=.028) and surface area occupied by tumor (p=.026). GZ21T also suppressed the progression of AKs to cSCC by decreasing the count (p=.047) and surface area (p=.049) of lesions more likely to represent cSCC. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (p=.026), Pi3K-Akt (p=.028), HIF-1 (p=.030), Wnt (p=.031), insulin (p=.011), and ErbB (p=.006) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK, while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/506864v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1254e6corg.highwire.dtl.DTLVardef@3fd190org.highwire.dtl.DTLVardef@1d75eb5org.highwire.dtl.DTLVardef@8afc97_HPS_FORMAT_FIGEXP M_FIG C_FIG