Berenguer Roque Aleksandra, Zgheib Alain, Salomon-Izquierdo Suslebys, Manso Peña Amanda, Osoria Alfonso Luis A, Piloto-Ferrer Janet, Annabi Borhane
Department of Experimental Oncology and Toxicology, Center for Pharmaceutical Research and Development, Havana, Cuba.
Chair in Cancer Prevention and Treatment, Département de Chimie, Université du Québec à Montréal, Succ. Centre-ville, Montreal, QC, C.P. 8888, Canada.
Discov Nano. 2025 May 19;20(1):83. doi: 10.1186/s11671-025-04257-z.
Poor water-solubility of emerging new chemotherapeutic drugs lead to low absorption and tissue bioavailability. Improved drug delivery has therefore recently been achieved through the versatile physico-chemical properties of nanocrystals (NCs) in targeted cancer therapies. Here, nanocrystalization was used with xanthatin, a not highly water-soluble natural sesquiterpene lactone compound that possesses anti-tumour properties and which was recently investigated for potential use in the treatment of cancer and autoimmune diseases. Given that tumour-promoting inflammation is a hallmark of colorectal cancer (CRC), and that epidemiological studies associated inflammatory biomarkers to CRC poor prognosis and therapy resistance, the anti-inflammatory properties of xanthatin NCs were assessed in 2D monolayers and in 3D spheroids of a human HT29 CRC cell model. The 3D spheroids being a model recapitulating a cancer stem cells and chemoresistant phenotype. HT29 2D monolayer cell response was first tested against four pro-inflammatory inducers including phorbol-12-myristate-13-acetate, tumour necrosis factor alpha (TNFα), transforming growth factor beta, and Concanavalin A. Of these inducers, HT29 cell response to TNFα resulted in the most elevated expression of cyclooxygenase (COX)-2 which was prevented by commercial xanthatin along with the phosphorylation of the extracellular signal-regulated kinase 1/2 and of IkappaB (IκB). Alteration of 3D spheroids formation and of the inflammatory/immunity transcriptomic signature was also found better altered by xanthatin NCs in comparison to commercial xanthatin and the isolated molecule. Collectively, our data indicate that xanthatin nanocrystallization did not alter the potential in vitro anti-inflammatory and anticancer properties of xanthatin against a 3D CRC chemoresistance cellular model. These properties make NCs a significant advancement in the field of cancer theranostics to improve patient outcomes.
新型化疗药物较差的水溶性导致其吸收和组织生物利用度较低。因此，最近通过纳米晶体（NCs）在靶向癌症治疗中的多种物理化学性质实现了药物递送的改善。在此，纳米晶化技术被应用于山苍子素，这是一种水溶性不高的天然倍半萜内酯化合物，具有抗肿瘤特性，最近被研究用于癌症和自身免疫性疾病的潜在治疗。鉴于促肿瘤炎症是结直肠癌（CRC）的一个标志，并且流行病学研究将炎症生物标志物与CRC的不良预后和治疗抗性相关联，因此在人HT29 CRC细胞模型的二维单层和三维球体中评估了山苍子素纳米晶体的抗炎特性。三维球体是一种模拟癌症干细胞和化疗抗性表型的模型。首先针对四种促炎诱导剂测试了HT29二维单层细胞反应，包括佛波醇-12-肉豆蔻酸酯-13-乙酸酯、肿瘤坏死因子α（TNFα）、转化生长因子β和伴刀豆球蛋白A。在这些诱导剂中，HT29细胞对TNFα的反应导致环氧合酶（COX）-2的表达升高最为明显，而市售的山苍子素以及细胞外信号调节激酶1/2和IκB（IκB）的磷酸化可阻止这种升高。与市售山苍子素和分离的分子相比，还发现山苍子素纳米晶体能更好地改变三维球体的形成以及炎症/免疫转录组特征。总体而言，我们的数据表明，山苍子素纳米晶化并未改变山苍子素对三维CRC化疗抗性细胞模型的体外抗炎和抗癌潜力。这些特性使纳米晶体在癌症治疗诊断领域取得了重大进展，以改善患者预后。
