Biology subjects

Josa-Cullere, L.

Publications and source records attributed to Josa-Cullere, L..

3 recordsLinked to original sources

bioRxiv2025

Photocaged chloroquine derivatives for the light-dependent inhibition of autophagy in cancer stem cells

Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit autophagy and have shown promise as adjuvant anticancer agents, particularly for targeting therapy-resistant cancer stem cells (CSCs). However, their clinical utility is limited by systemic toxicity and poor tumour selectivity. Here we report the design, synthesis, and photochemical evaluation of [7-(diethylamino)coumarin-4-yl]methyl (DEACM)-caged CQ and HCQ derivatives as visible-light-activated autophagy inhibitors. Selective caging of the aliphatic amine fully suppressed biological activity in the dark and enabled rapid, efficient release of the parent drugs upon illumination. The lead compound 1C displayed robust light-dependent cytotoxicity across multiple cancer cell lines and, upon photoactivation, recapitulated CQs effects on LC3-II accumulation. In CSC-enriched tumourspheres, illumination of 1C completely abolished spheroid formation, demonstrating precise spatiotemporal control of stemness suppression. Importantly, ex vivo and in vivo studies confirmed that visible light penetrates tumour tissue sufficiently to activate 1C and release CQ within the tumour. These findings establish the first proof of concept for light-controlled autophagy inhibition and provide a blueprint for spatiotemporally confined anticancer therapies based on photopharmacological modulation of CSCs.

cancer biology↗

bioRxiv2024

HDAC inhibitor derivatives induce differentiation of leukemic cells through two distinct and separable mechanisms

Acute myeloid leukaemia (AML) is a haematopoietic malignancy comprising different genetic subtypes with a common hallmark of differentiation arrest. In abnormal haematopoiesis, overcoming the differentiation blockade has emerged as an attractive therapeutic strategy. In a screen with genetically distinct AML cell lines, histone deacetylase inhibitors (HDACis) were observed to cause an upregulation in the expression of CD11b, a myeloid differentiation marker. These caused changes in cell morphology, block in proliferation, and cell cycle arrest at the G1 phase. To gain insights onto the mechanism of these compounds, we planned to prepare inactive probes devoid of the zinc binding motif. However, these compounds were unexpectedly still able to initiate differentiation, albeit through a distinct target and via a G2 arrest. Subsequent RNA sequencing studies supported the differentiation phenotype for the HDACis and highlighted the role of cell cycle regulatory kinases for the effect observed in the probe molecules. We then showed that these inhibit Aurora A and GSK3 kinases, suggesting their potential as therapeutic targets for differentiation therapy in AML. Our work supports the importance of properly validating inactive tool compounds and their potential to identify novel targets.

pharmacology and toxicology↗

bioRxiv2021

A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells

Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

cancer biology↗