Dis Colon Rectum. 2023 Jan 4. doi: 10.1097/DCR.0000000000002623. Online ahead of print.
ABSTRACT
BACKGROUND: Anal cancer is associated with high-risk human papillomavirus infection and oncoprotein expression. We have identified several protease inhibitors, used to treat HIV, that decrease oncogene expression.
OBJECTIVE: The aim of this project is to determine whether the protease inhibitor, Saquinavir, results in a treatment response in anal cancer spheroids.
DESIGN: K14E6/E7 transgenic mice (n=5), which express HPV16 oncoproteins E6 and E7 in their epithelium, were treated topically at the anus with carcinogen, 7,12 dimethylbenz[a]anthracene, to promote anal tumor growth. Tumors were excised and digested, and cells were plated. The tumor cells form 3D multicellular aggregates, known as spheroids.
SETTINGS: This study was performed in an American Association for Accreditation of Laboratory Animal Care approved facility.
INTERVENTIONS: Spheroids were placed in treatment groups: no treatment, vehicle (dimethyl sulfoxide), and 15 μM Saquinavir. Spheroids were imaged immediately prior to treatment and 24-hours post-treatment.
MAIN OUTCOME MEASURES: Spheroid diameters were measured using ImageJ and mean percent reduction was calculated for each spheroid to determine treatment effect on spheroid growth. Analysis of variance using pairwise comparisons were performed with Fisher’s protected least significant difference tests.
RESULTS: No treatment (n=119 spheroids) and vehicle (n=126 spheroids) groups demonstrated an increase in spheroid diameter over the treatment period. In contrast, spheroids treated with Saquinavir (n=151 spheroids), demonstrated a statistically significant percent reduction compared to no treatment (p value < 0.0001) and vehicle (p value = 0.002) groups.
LIMITATIONS: A limitation of this data is that some human error is likely present given that images were analyzed by three different scientists.
CONCLUSIONS: Saquinavir leads to a statistically significant percent reduction in mice anal tumor spheroid growth ex-vivo when compared to control groups. Protease inhibitor therapy may be an effective treatment or adjuvant therapy to the Nigro protocol to promote anal cancer tumor regression. See Video Abstract at http://links.lww.com/DCR/C82.
PMID:36599112 | DOI:10.1097/DCR.0000000000002623
