Document details

Anticancer activity of benzo[a]phenoxazine compounds promoting lysosomal dysfunction

Author(s): Ferreira, João Carlos Canossa ; Gonçalves, M. Sameiro T. ; Preto, Ana ; Sousa, Maria João

Date: 2024

Persistent ID: https://hdl.handle.net/1822/94800

Origin: RepositóriUM - Universidade do Minho

Project/scholarship: info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F133207%2F2017/PT; info:eu-repo/grantAgreement/FCT/POR_NORTE/COVID%2FBD%2F151978%2F2021/PT; info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04050%2F2020/PT; info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00686%2F2020/PT; info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-QIN%2F28662%2F2017/PT;

Subject(s): Nile Blue analogue; benzo[a]phenoxazine; anticancer drug; colorectal cancer; breast cancer; lysosome membrane permeabilization; Ciências Naturais::Ciências Químicas; Ciências Naturais::Ciências Biológicas


Description

Specific cancer therapy remains a problem to be solved. Breast and colorectal cancer are among the cancers with the highest prevalence and mortality rates. Although there are some therapeutic options, there are still few effective agents for those cancers, which constitutes a clinical problem that requires further research efforts. Lysosomes play an important role in cancer cells’ survival, and targeting lysosomes has gained increased interest. In recent years, our team has been synthetizing and testing novel benzo[a]phenoxazine derivatives, as they have been shown to possess potent pharmacological activities. Here, we investigated the anticancer activity of three of the most potent derivatives from our library, C9, A36, and A42, on colorectal- and breast-cancer-derived cell lines, and compared this with the effect on non-neoplastic cell lines. We observed that the three compounds were selective for the cancer cells, namely the RKO colorectal cancer cell line and the MCF7 breast cancer cell line. In both models, the compounds reduced cell proliferation, cell survival, and cell migration, accumulated on the lysosome, and induced cell death accompanied by lysosomal membrane permeabilization (LMP), increasing the intracellular pH and ROS accumulation. Our results demonstrated that these compounds specifically target lysosomes from cancer cells, making them promising candidates as LMP inducers for cancer therapy.

Doctoral Grant J. Canossa Ferreira SFRH/BD/133207/2017 and COVID/BD/151978/2021 acknowledged to Fundação para a Ciência e Tecnologia. This work was supported by the strategic programmes UID/BIA/04050/2020 and UID/QUI/0686/2020 funded by national funds through the FCT I.P. Thanks are due to FCT for financial support to the Portuguese NMR network (PTNMR, Bruker Avance III 400-Univ. Minho). This work was also funded by FCT within the scope of project PTDC/QUI-QIN/28662/2017.

Document Type Journal article
Language English
Contributor(s) Universidade do Minho
CC Licence
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