Evaluation of the anticancer effects exerted by 5-fluorouracil and heme oxygenase-1 inhibitor hybrids in HTC116 colorectal cancer cells

Abstract

Colon cancer remains a clinical challenge in industrialised countries. Its treatment with 5-Flurouracil (5-FU) develops many side effects and resistance. Thus, several strategies have been undertaken so far, including the use of drug cocktails and polypharmacology. Heme oxygenase-1 (HO-1) is an emerging molecular target in the treatment of various cancers. We recently demonstrated that a combination of HO-1 inhibitors with 5-FU and the corresponding hybrids SI1/17, SI1/20, and SI1/22, possessed anticancer activity against prostate and lung cancer cells. In this work, we evaluated these hybrids in a model of colon cancer and found that SI1/22 and the respective combo have greater potency than 5-FU. Particularly, compounds inhibit HO-1 activity in cell lysates, increase ROS and the expression of HO-1, SOD, and Nrf2. Moreover, we observed a decrease of pro-caspase and an increase in cleaved PARP-1 and p62, suggesting apoptotic and autophagic cell death and potential application of these drugs as anticancer agents.

Keywords:

• Hybrids
• mutual prodrugs
• 5-fluorouracil
• heme oxygenase 1
• HTC116 colorectal cancer cells

Author contributions

Conceptualisation, M.G. and S.I.; methodology, L.S., A.N., V.S., M.G., S.I.; validation M.G. and S.I.; synthesis, purification, and compounds characterisation, L.S., V.P., S.I.; contributed reagents, materials, and analysis tools, V.S., L.V., M.G., S.I.; formal analysis, L.S., V.S. M.G., S.I.; investigation, A.N., V.C., F.A., V.P., L.V.; data curation, L.S., A.N., F.A., V.C., M.G., S.I.; writing original draft preparation, L.S., M.G., S.I.; writing, review and editing, L.S., M.G., S.I.; visualisation, A.N., L.V., V.C.; supervision, L.S., M.G., S.I.; funding acquisition, M.G. and S.I. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The data that support this study are available from the corresponding authors upon reasonable request.

Additional information

Funding

This study was supported from the Project HO-Hybrid2 (P2022F4PTE, CUP Master E53D23015960001, granted to S.I), through the National Recovery and Resilient Plan (PNRR) Mission 4, Component 2, Investiment 1.1, call for tender “Bando PRIN 2022 PNRR” No. 1409, published on 14/09/2022 by the Italian Ministry of University and Research (MUR), funded by European Union - NexGenerationEU plan; and from a grant of the University of Palermo (FFR-D15_006475, 2018/2021).