Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A6, 62500 Brno, Czech Republic.
Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
Int J Mol Sci. 2023 Oct 20;24(20):15405. doi: 10.3390/ijms242015405.
Defects in cell death signaling pathways are one of the hallmarks of cancer and can lead to resistance to conventional therapy. Natural products are promising compounds that can overcome this resistance. In the present study we studied the effect of six quaternary benzophenanthridine alkaloids (QBAs), sanguinarine, chelerythrine, sanguirubine, chelirubine, sanguilutine, and chelilutine, on Jurkat leukemia cells, WT, and cell death deficient lines derived from them, CASP3/7/6 and FADD, and on solid tumor, human malignant melanoma, A375 cells. We demonstrated the ability of QBAs to overcome the resistance of these deficient cells and identified a novel mechanism for their action. Sanguinarine and sanguirubine completely and chelerythrine, sanguilutine, and chelilutine partially overcame the resistance of CASP3/7/6 and FADD cells. By detection of cPARP, a marker of apoptosis, and pMLKL, a marker of necroptosis, we proved the ability of QBAs to induce both these cell deaths (bimodal cell death) with apoptosis preceding necroptosis. We identified the new mechanism of the cell death induction by QBAs, the downregulation of the apoptosis inhibitors cIAP1 and cIAP2, i.e., an effect similar to that of Smac mimetics.
细胞死亡信号通路的缺陷是癌症的特征之一，可导致对常规治疗的耐药性。天然产物是有前途的化合物，可以克服这种耐药性。在本研究中，我们研究了六种季铵苯并菲啶生物碱（QBAs），血根碱、白屈菜红碱、血根碱、白屈菜红碱、血根灵和白屈菜红灵对 Jurkat 白血病细胞、WT 细胞以及源自它们的细胞死亡缺陷系，CASP3/7/6 和 FADD，以及对实体瘤、人恶性黑色素瘤 A375 细胞的影响。我们证明了 QBAs 克服这些缺陷细胞耐药性的能力，并确定了它们作用的新机制。血根碱和血根灵完全，白屈菜红碱、血根灵和白屈菜红灵部分克服了 CASP3/7/6 和 FADD 细胞的耐药性。通过检测细胞凋亡的标志物 cPARP 和坏死的标志物 pMLKL，我们证明了 QBAs 诱导这两种细胞死亡（双模态细胞死亡）的能力，即凋亡先于坏死。我们确定了 QBAs 诱导细胞死亡的新机制，即凋亡抑制剂 cIAP1 和 cIAP2 的下调，即类似于 Smac 模拟物的作用。
