Wiraswati Hesti Lina, Bashari Muhammad Hasan, Alfarafisa Nayla Majeda, Ma'ruf Ilma Fauziah, Sholikhah Eti Nurwening, Wahyuningsih Tutik Dwi, Satriyo Pamungkas Bagus, Mustofa Mustofa, Satria Denny, Damayanti Ema
Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Oncology and Stem Cells Working Group, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Adv Appl Bioinform Chem. 2024 Feb 27;17:33-46. doi: 10.2147/AABC.S452281. eCollection 2024.
Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary.
In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid.
Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-β tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-β tubulin disintegration.
The results show that this combination is promising for further in vitro and in vivo studies.
多种癌症类型中的多药耐药性是癌症治疗的主要障碍。单一药物分子靶点的概念往往会因细胞过程的复杂性而导致治疗失败。因此，联合化疗（同时使用两种或更多种抗癌药物）可以克服这个问题，因为它除了降低耐药性和药物剂量外，还可能具有协同疗效。此前，我们报道吡唑啉B在计算机模拟和体外研究中均具有良好的抗癌活性。为了提高这种药物的疗效，有必要与阿霉素和紫杉醇等已确立的抗癌药物联合使用。
在本研究中，我们使用计算机模拟方法，利用各种计算框架预测吡唑啉B与紫杉醇或阿霉素的协同作用，并将结果与关于阿霉素 - 环磷酰胺和紫杉醇 - 抗坏血酸联合使用的既定研究结果进行比较。
药物相互作用分析表明，该联合用药安全，无禁忌证或副作用。此外，分子对接研究表明，阿霉素 - 吡唑啉B和阿霉素 - 环磷酰胺可能通过抑制拓扑异构酶I与DNA链的结合来协同抑制癌细胞增殖。此外，吡唑啉B - 紫杉醇组合可能具有协同活性，通过抑制Bcl2与Bax片段的结合导致细胞凋亡，或通过抑制α - β微管蛋白解聚来抑制细胞分裂。紫杉醇 - 抗坏血酸对抑制α - β微管蛋白解聚具有协同作用。
结果表明，这种联合用药有希望进一步进行体外和体内研究。
