Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

Abstract

Hesti Lina Wiraswati,1,2 Muhammad Hasan Bashari,1,2 Nayla Majeda Alfarafisa,1,2 Ilma Fauziah Ma’ruf,3 Eti Nurwening Sholikhah,4 Tutik Dwi Wahyuningsih,5 Pamungkas Bagus Satriyo,4 Mustofa Mustofa,4 Denny Satria,6 Ema Damayanti7 1Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; 2Oncology and Stem Cells Working Group, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia; 3Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency, Bogor, Indonesia; 4Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; 5Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta, Indonesia; 6Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia; 7Research Center for Food Technology and Processing, National Research and Innovation Agency, Gunungkidul, IndonesiaCorrespondence: Hesti Lina Wiraswati, Department of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Bandung, 40161, Indonesia, Tel [phone], Fax [phone], Email [email protected]: 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.Materials and Methods: 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.Results and Discussion: 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.Conclusion: The results show that this combination is promising for further in vitro and in vivo studies.Keywords: doxorubicin, in silico study, pyrazoline B, paclitaxel, synergistic effect

Keywords

• doxorubicin
• in silico study
• pyrazoline b
• paclitaxel
• synergistic effect