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A new alkaloid, belonging to the pretazettine group of Amaryllidaceae alkaloids, was isolated from dried bulbs of Narcissus jonquilla quail and named jonquailine. Its structure, including the absolute configuration, was elucidated using various NMR, ECD and ESI MS techniques. Initial biological evaluation revealed significant antiproliferative effects against glioblastoma, melanoma, uterine sarcoma and non-small-cell lung cancer cells displaying various forms of drug resistance, including resistance to apoptosis and multi-drug resistance. Jonquailine was also found to synergize with paclitaxel in its antiproliferative action against drug-resistant lung cancer cells. The results obtained compared with literature data also showed that the hydroxylation at C-8 is an important feature for the anticancer activity but this seems unaffected by the stereochemistry or the acetalization of the lactol.

Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC50 growth inhibitory values between 30–100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine.—Van Goietsenoven, G., Hutton, J., Becker, J.-P., Lallemand, B., Robert, F., Lefranc, F., Pirker, C., Vandenbussche, G., Van Antwerpen, P., Evidente, A., Berger, W., Prévost, M., Pelletier, J., Kiss, R., Goss Kinzy, T., Kornienko, A., Mathieu, V. Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas.

As a continuation of the studies aimed at the development of new anticancer agents derived from the Amaryllidaceae alkaloid lycorine, 35 C1,C2-ether analogues of this natural product were synthesized. The compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines with varied levels of apoptosis resistance. A strong correlation between the compound lipophilicity and anticancer activity was observed, indicating that cell permeability properties must be an important determinant in the design of lycorine-based anticancer agents. A theoretical docking model, consistent with the experimental observations, is presented.

Purpose To design and synthesize chemoembolization particles for the delivery of Ophiobolin A (OphA), a promising fungal-derived chemotherapeutic, directly at the tumour location. To investigate cell death mechanism of OphA on a Rhabdomyosarcoma cancer (RD) cell line. Rhabdomyosarcoma is the most common soft tissue sarcoma in children; with a 5-year survival rate of between 30 and 65%. Methods Multimodal chemoembolization particles were prepared by sintering mesoporous silica nanoparticles, prepared by the sol-gel method, onto the surface of polystyrene microspheres, prepared by suspension copolymerisation. The chemoembolization particles were subsequently loaded with OphA. The effects of OphA in vitro were characterised by flow cytometry and nanoparticle tracking analysis (NanoSight). Results High loading of OphA onto the chemoembolization particles was achieved. The subsequent release of OphA onto RD cells in culture showed a 70% reduction in cell viability. OphA caused RD cells to round up and their membrane to bleb and caused cell death via apoptosis. OphA caused both an increase in the number of microvesicles produced and an increase in DNA content within these microvesicles. Conclusions The prepared chemoembolization particles showed good efficacy against RD cells in culture.