Synergistic induction of apoptosis in cancer cells by combined silver nanoparticles and paclitaxel

Document Type : Original Article

Authors

1 Department of Anatomy, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

2 School of Medicine, Iran University of Medical Sciences, Tehran, Iran

3 Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran

10.22038/ijbms.2026.90764.19567

Abstract

Objective(s): Even with treatment, cervical cancer continues to be rampant among females and has the highest mortality. Carrier system therapies, which combine cancer drugs with nanoparticles, are purported to arrest tumor growth and minimize the side effects of cancer drugs. We envisioned paclitaxel-loaded silver nanoparticles (PTX-AgNPs) as an appropriate carrier for targeting cancer cells. Hence, we studied the effects of paclitaxel (PTX) and silver nanoparticles (AgNPs) as an adjunct therapy in the management of cervical cancer.
Materials and Methods: Anti-cancer activity with PTX alone or in combination with AgNPs was assessed by MTT assay and real-time PCR. The mechanism underlying the antiproliferative effects was investigated by measuring the expression of apoptotic markers (Bax, Caspase-3, Bak) and anti-apoptotic markers (Bcl-2, Mcl-1) by RT-PCR. 
Results: PTX and silver nanoparticles alone induced apoptosis; however, at lower doses, they showed synergism, with an inhibitory concentration of 50% (IC50). Real-time PCR showed that the combination treatment, PTX and AgNPs, significantly increased the mRNA expression of the Bax, Bak, and Caspase-3 genes in the HeLa cell line compared with mono-treatment (P<0.05). Anti-apoptotic Bcl-2 and Mcl-1 mRNA levels were also decreased in all treated groups as compared to control cells. 
Conclusion: We showed that silver nanoparticles have a synergistic effect with PTX and were able to give favorable results (higher cell death in the combined group) at lower concentrations of PTX.

Keywords

Main Subjects


1. Kweik OMA, Hamid MAA, Sheqlieh SO, Abu-Nasser BS, Abu-Naser SS. Artificial neural network for lung cancer detection. Int J Acad Eng Res 2020;4:1-7.
2. Aredo MA, Sendo EG, Deressa JT. Knowledge of cervical cancer screening and associated factors among women attending maternal health services at Aira Hospital, West Wollega, Ethiopia. SAGE Open Med 2021;9:20503121211047063.
3. Walter FM, Mwaka AD, Neal RD. Achieving earlier diagnosis of symptomatic cervical cancer. Br J Gen Pract 2014;64:495–496.
4. Hakim RU, Amin T, Ul Islam SB. Advances and challenges in cervical cancer: From molecular mechanisms and global epidemiology to innovative therapies and prevention strategies. Cancer Control 2025;32:10732748251336415.
5. Alrushaid N, Khan FA, Al-Suhaimi EA, Elaissari A. Nanotechnology in cancer diagnosis and treatment. Pharmaceutics 2023;15:1025.
6. Daei S, Ziamajidi N, Abbasalipourkabir R, Aminzadeh Z, Vahabirad M. Silver nanoparticles exert apoptotic activity in bladder cancer 5637 cells through alteration of Bax/Bcl-2 genes expression. Chonnam Med J 2022;58:102–109.
7. Xiaoxia X, Jing S, Dongbin X, Yonggang T, Jingke Z, Hulai W. Realgar nanoparticles inhibit migration, invasion and metastasis in a mouse model of breast cancer by suppressing matrix metalloproteinases and angiogenesis. Curr Drug Deliv 2020;17:148–158.
8. Wang X, Wang L, Zong S, Qiu R, Liu S. Use of multifunctional composite nanofibers for photothermal chemotherapy to treat cervical cancer in mice. Biomater Sci. 2019;7:3846–3854.
9. Kelly KL, Coronado E, Zhao LL, Schatz GC. The optical properties of metal nanoparticles: the influence of size, shape, and dielectric environment. J Phys Chem B 2003;107:668–677.
10. Ansari MA, Asiri SMM, Alzohairy MA, Alomary MN, Almatroudi A, Khan FA. Biofabricated fatty acids-capped silver nanoparticles as potential antibacterial, antifungal, antibiofilm and anticancer agents. Pharmaceuticals 2021;14:139.
11. Baharara J, Ramezani T, Hosseini N, Mousavi M. Silver nanoparticles synthesized coating with Zataria multiflora leaves extract induced apoptosis in HeLa cells through p53 activation. Iran J Pharm Res 2018;17:627–639.
12. Zenjanab MK, Alimohammadvand S, Doustmihan A, Kianian S, Oskouei BS, Mazloomi M, et al. Paclitaxel for breast cancer therapy: A review on effective drug combination modalities and nano drug delivery platforms. J Drug Deliv Sci Technol 2024;95:105567.
13. Alalawy AI. Key genes and molecular mechanisms related to paclitaxel resistance. Cancer Cell Int 2024;24:244.
14. Gasca J, Flores ML, Giráldez S, Ruiz-Borrego M, Tortolero M, Romero F, et al. Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer. Oncotarget 2016;7:52751–52765.
15. Castilla C, Flores ML, Medina R, Pérez-Valderrama B, Romero F, Tortolero M, et al. Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1. Mol Cancer Ther 2014;13:2372–2383.
16. Tunç T, Hepokur C, Kariper A. Synthesis and characterization of paclitaxel-loaded silver nanoparticles: Evaluation of cytotoxic effects and antimicrobial activity. Bioinorg Chem Appl 2024;2024:9916187.
17. Aboul-Nasr MB, Yasien AA, Mohamed SS, Aboul-Nasr YB, Obiedallah M. Exploring the anticancer potential of green silver nanoparticles–paclitaxel nanocarrier on MCF-7 breast cancer cells. Sci Rep 2025;15:20198.
18. Ankireddy K, Iskander M, Vunnam S, Anagnostou DE, Kellar J, Cross W. Thermal analysis of silver nanoparticles for flexible printed antenna fabrication. J Appl Phys 2013;114:124303.
19. Danışman-Kalındemirtaş F, Kariper İA, Hepokur C, Erdem-Kuruca S. Selective cytotoxicity of paclitaxel bonded silver nanoparticle on different cancer cells. J Drug Deliv Sci Technol 2021;61:102265.
20. Baladi M, Amiri M, Amirinezhad M, Abdulsahib WK, Pishgouii F, Golshani Z, et al. Green synthesis and characterization of terbium orthoferrite nanoparticles decorated with g-C3N4 for antiproliferative activity. Arab J Chem 2023;16:104841.
21. Amiri M, Basiri M, Eskandary H, Akbarnejad Z, Esmaeeli M, Masoumi-Ardakani Y, et al. Cytotoxicity of carboplatin on human glioblastoma cells is reduced by electromagnetic field. Electromagn Biol Med 2018;37:138–145.
22. Yahyapour R, Khoei S, Kordestani Z, Larizadeh MH, Jomehzadeh A, Amirinejad M, et al. Comparative study of electromagnetic field and temozolomide administration. Curr Radiopharm 2023;16:123–132.
23. Amirinejad M, Eftekhar-Vaghefi SH, Nematollahi Mahani SN, Salari M, Yahyapour R, Ahmadi-Zeidabadi M. Exposure to low-frequency radiation changes apoptosis markers. Curr Radiopharm 2024;17:55–67.
24. He H, Ni J, Huang J. Molecular mechanisms of chemoresistance in osteosarcoma. Oncol Lett 2014;7:1352–1362.
25. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell 2014;25:2677–2681.
26. Mokhtari RB, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget 2017;8:38022–38043.
27. Smith HA, Kang Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med 2013;91:411–429.
28. Choudhari AS, Mandave PC, Deshpande M, Ranjekar P, Prakash O. Phytochemicals in cancer treatment. Front Pharmacol 2020;10:1614.
29. Li J, Zhang S, Paik KW, Wong YH, He P, Zhang S. Present status and prospects of nano-silver particles. J Adhes Sci Technol 2025;39:281–318.
30. Kanwar R, Fatima R, Kanwar R, Javid M, Muhammad U, Ashraf Z, et al. Biological, physical and chemical synthesis of silver nanoparticles. Pure Appl Biol 2022; 11:418-435
31. Dhaka A, Mali SC, Sharma S, Trivedi R. A review on biological synthesis of silver nanoparticles and their potential applications. Results Chem 2023;6:101108.
32. Kim TH, Kim M, Park HS, Shin US, Gong MS, Kim HW. Size-dependent cellular toxicity of silver nanoparticles. J Biomed Mater Res A 2012;100:1033–1043.
33. Cheon JY, Kim SJ, Rhee YH, Kwon OH, Park WH. Shape-dependent antimicrobial activities of silver nanoparticles. Int J Nanomedicine 2019;14:2773–2780.
34. Raza MA, Kanwal Z, Rauf A, Sabri A, Riaz S, Naseem S. Size- and shape-dependent antibacterial studies of silver nanoparticles synthesized by wet chemical routes. Nanomaterials (Basel) 2016;6:74.
35. Cheng EHY, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, et al. Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 1997;278:1966–1968.
36. Kang MH, Reynolds CP. Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009;15:1126–1132.
37. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 2008;18:157–164.
38. Alqahtani FY, Aleanizy FS, El Tahir E, Alkahtani HM, AlQuadeib BT. Paclitaxel. Profiles Drug Subst Excip Relat Methodol 2019;44:205–238.
39. Pal MK, Jaiswar SP, Dwivedi A, Goyal S, Dwivedi VN, Pathak AK, et al. Synergistic effect of graphene oxide coated nanotised apigenin with paclitaxel. Anticancer Agents Med Chem 2017;17:1721–1732.
40. Kim KS, Cho CH, Park EK, Jung MH, Yoon KS, Park HK. AFM-detected apoptotic changes caused by paclitaxel in HeLa cells. PLoS One 2012;7:e30066.
41. Aborehab NM, Osama N. Effect of gallic acid in potentiating chemotherapeutic effect of paclitaxel in HeLa cervical cancer cells. Cancer Cell Int 2019;19:154.
42. Xin L, Wang J, Fan G, Che B, Wu Y, Guo S, et al. Oxidative stress and mitochondrial injury-mediated cytotoxicity induced by silver nanoparticles. Environ Toxicol 2016;31:1691–1699.
43. Holmila RJ, Vance SA, King SB, Tsang AW, Singh R, Furdui CM. Silver nanoparticles induce mitochondrial protein oxidation in lung cells. Antioxidants (Basel) 2019;8:552.
44. Ma J, Di Z, Lu H, Huang W, Yu D. ASK1 activation involved in silver nanoparticle-induced apoptosis of lung cancer cells. J Biomed Nanotechnol 2017;13:349–354.
45. Li J, Chang X, Shang M, Niu S, Zhang W, Zhang B, et al. Mitophagy–lysosomal pathway involved in silver nanoparticle-induced apoptosis. Ecotoxicol Environ Saf 2021;208:111463.
46. Ullah I, Khalil AT, Ali M, Iqbal J, Ali W, Alarifi S, et al. Green-synthesized silver nanoparticles induce apoptotic cell death in breast cancer cells. Oxid Med Cell Longev 2020;2020:1215395.
47. Chairuangkitti P, Lawanprasert S, Roytrakul S, Aueviriyavit S, Phummiratch D, Kulthong K, et al. Silver nanoparticles induce toxicity via ROS-dependent pathways. Toxicol In Vitro 2013;27:330–338.
48. Foldbjerg R, Dang DA, Autrup H. Cytotoxicity and genotoxicity of silver nanoparticles in lung cancer cells. Arch Toxicol 2011;85:743–750.
49. Manivasagan P, Venkatesan J, Senthilkumar K, Sivakumar K, Kim SK. Biosynthesis and cytotoxic effect of silver nanoparticles. Biomed Res Int 2013;2013:287638.
50. Aygün A, Gülbağça F, Nas MS, Alma MH, Çalımlı MH, Ustaoglu B, et al. Biological synthesis of silver nanoparticles and anticancer potential. J Pharm Biomed Anal 2020;179:113012.
51. Yuan YG, Zhang S, Hwang JY, Kong IK. Silver nanoparticles potentiate cytotoxicity in cervical cancer cells. Oxid Med Cell Longev 2018;2018:6121328.
52. Muhammad N, Zhao H, Song W, Gu M, Li Q, Liu Y, et al. Silver nanoparticles functionalized paclitaxel nanocrystals enhance anticancer effect. Nanotechnology. 2021;32:085105.
53. Rose PG, Blessing JA, Gershenson DM, McGehee R. Paclitaxel and cisplatin as first-line therapy in cervical cancer. J Clin Oncol. 1999;17:2676–2680.
54. Li Y, Guo M, Lin Z, Zhao M, Xiao M, Wang C, et al. Silver nanoparticle-based co-delivery of paclitaxel induces apoptosis. Int J Nanomedicine. 2016;11:6693–6702.
55. Rudrappa M, Rudayni HA, Assiri RA, Bepari A, Basavarajappa DS, Nagaraja SK, et al. Green synthesis of silver nanoparticles exhibits anticancer activity. Nanomaterials (Basel). 2022;12:493.
56. Alsadooni JFK, Haghi M, Barzegar A, Feizi MAH. Chitosan hydrogel containing nanoparticle complex with paclitaxel on cancer cells. Int J Biol Macromol. 2023;247:125612.
57. Aborehab NM, Elnagar MR, Waly NE. Gallic acid potentiates apoptotic effect of paclitaxel via Bax overexpression. J Biochem Mol Toxicol. 2021;35:e22638.
58. Subramaniam Y, Subban K, Chelliah J. Synergistic anticancer effect of fungal compound and paclitaxel in cervical cancer. Toxicol In Vitro 2021;72:105079.
59. Al-Khedhairy AA, Wahab R. Silver nanoparticles anticancer activity against liver and breast cancer cells. Metals (Basel) 2022;12:148.
60. Sangour MH, Ali IM, Atwan ZW, Al Ali AAALA. Effect of Ag nanoparticles on viability of MCF-7 and Vero cell lines and gene expression of apoptotic genes. Egypt J Med Hum Genet 2021;22:9.