Department of Medicine and General Cytometry Service-Nucleus, CIBERONC CB16/12/00400, Cancer Research Centre (IBMCC/CSIC/USAL/IBSAL), IBSAL, University of Salamanca-CSIC, Campus Miguel de Unamuno s/n, 37007 Salamanca, Spain.
Department of Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, Faculty of Pharmacy, University of Salamanca, Campus Miguel de Unamuno s/n, 37007 Salamanca, Spain.
Int J Mol Sci. 2024 Apr 24;25(9):4631. doi: 10.3390/ijms25094631.
When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis.
当发现新的抗肿瘤治疗药物时，从化学结构的角度研究新的靶分子，并进行高效、系统的评估至关重要。对于天然产物及其衍生化合物，研究化学调节以进一步探索抗肿瘤药理活性尤为重要。在这项工作中，我们评估了环木脂素衍生化合物鬼臼醛作为一种新型抗肿瘤化合物的潜力，包括其对细胞周期的影响和对细胞内信号转导的影响。我们使用功能蛋白质组学特征评估来进行评价。与美国食品和药物管理局批准的药物依托泊苷（另一种鬼臼毒素衍生物）相比，我们发现了鬼臼醛细胞毒性方面的有趣结果。此外，我们还观察到了处理细胞有丝分裂阻滞的效果。与依托泊苷相比，鬼臼醛在实体肿瘤细胞系中的细胞毒性更强，并且比依托泊苷更成功地阻断了细胞周期。对失调蛋白的高通量分析揭示了鬼臼醛在 HT-29 细胞系中的选择性抗有丝分裂作用机制，与其他实体瘤和血液瘤系不同。此外，我们还解析了鬼臼醛的凋亡特征。细胞死亡机制独立于细胞周期特征而被激活。这些靶向分析的结果还表明，对激酶信号的显著反应，这些激酶是参与细胞增殖或转移信号级联反应的关键蛋白。通过对鬼臼醛的全面分析，发现了其显著的细胞毒性、抗有丝分裂和其他抗肿瘤特性，这将为该化合物的进一步化学转化和抗肿瘤分析提供新的方向。
