Resveratrol Enhances Gemcitabine-Induced Apoptosis in A549 Non-Small Cell Lung Cancer Cells

Main Article Content

Muneer Mohammed Hanoon
Yassir Mustafa Kamal Al Mulla Hummadi
Abdulwahid Abdulwahab Alnakal
Baydaa Hameed Abdullah

Abstract

Background: Lung cancer is the commonest cause of cancer related mortality. Non-small cell lung cancer (NSCLC) is the most prevalent kind of lung malignancies. Gemcitabine is a first line drug used in NSCLC. However, the therapeutic efficacy of gemcitabine is constrained by the drug resistance and toxicity. Resveratrol is a natural polyphenol with chemosensitizing properties, enhancing the antitumor effects of chemotherapy.


Objectives: To investigate whether resveratrol potentiates the apoptotic effect of gemcitabine in A549 cells and the modulatory effects of gemcitabine- resveratrol combination on PI3K/Akt and STAT3 pathways.


Methods: Exponentially growing A549 cells were treated with gemcitabine, resveratrol, or their combination. Annexin V-fluorescein isothiocyanate (Annexin V-FITC)/propidium iodide (PI) staining was used to measure apoptosis. The protein expression levels of phospho-Akt and phospho-STAT3 were quantified using Western blotting.


Results: The results indicated that gemcitabine-resveratrol combination greatly increased the apoptosis in A549 cells compared with single drug treatments. Moreover, the co-treatment significantly reduced the expression levels of phospho-Akt and phospho-STAT3 compared to each drug alone.


Conclusion: Resveratrol enhanced gemcitabine-induced apoptosis in A549 cells. Moreover, the combination treatment resulted in augmented suppression of both phospho-Akt and phospho-STAT3 expression. These findings suggest resveratrol as potential adjunct to gemcitabine to in the treatment of NSCLC.  

Article Details

Section

Articles

Author Biography

Baydaa Hameed Abdullah, Department of Clinical Laboratory Sciences, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

Clinical Biochemistry

How to Cite

Resveratrol Enhances Gemcitabine-Induced Apoptosis in A549 Non-Small Cell Lung Cancer Cells. (2026). Al Mustansiriyah Journal of Pharmaceutical Sciences, 26(2), 281-291. https://doi.org/10.32947/ajps.v26i2.1384

References

1- Mustafa E, RAJAB NA. Preparation and in-vitro evaluation of Paclitaxel-loaded sericin nanoparticles planned for pulmonary drug delivery system. ACTA Pharmaceutica Sciencia.63(2).

2- Tong Z, Wang Z, Jiang J, Fu W, Hu S. Glycyrrhizin enhances the antitumor activity of cisplatin in non‑small cell lung cancer cells by influencing DNA damage and apoptosis. Oncology Letters. 2025;29(4):207. DOI: https://doi.org/10.3892/ol.2025.14954

3- Chen C-P, Hung T-H, Hsu P-C, Yeh C-N, Huang W-K, Pan Y-R, et al. Synergistic effects of MK-1775 and gemcitabine on cytotoxicity in non-small cell lung cancer. Heliyon. 2024;10(22). DOI: https://doi.org/10.1016/j.heliyon.2024.e40299

4- Effendi WI, Nagano T, Tachihara M, Umezawa K, Kiriu T, Dokuni R, et al. Synergistic interaction of gemcitabine and paclitaxel by modulating acetylation and polymerization of tubulin in non-small cell lung cancer cell lines. Cancer Management and Research. 2019:3669-79. DOI: https://doi.org/10.2147/CMAR.S193789

5- Zhang X, Qi B, Chen J. Clinical application and drug resistance mechanism of gemcitabine. Frontiers in Cell and Developmental Biology. 2025;13:1702720. DOI: https://doi.org/10.3389/fcell.2025.1702720

6- Jiang S, Wang R, Zhang X, Wu F, Li S, Yuan Y. Combination treatment of gemcitabine and sorafenib exerts a synergistic inhibitory effect on non-small cell lung cancer in vitro and in vivo via the epithelial-to-mesenchymal transition process. Oncology Letters. 2020;20(1):346-56. DOI: https://doi.org/10.3892/ol.2020.11536

7- Karabat MU, Tuncer MC. Synergistic Induction of Apoptosis by Boswellic Acid and Cisplatin in A549 Lung Cancer Cells Through NF-κB Modulation and p53 Pathway Activation. Current Issues in Molecular Biology. 2025;47(9):785. DOI: https://doi.org/10.3390/cimb47090785

8- Lin Y-h, Zhu L-y, Yang Y-q, Zhang Z-h, Chen Q-g, Sun Y-p, et al. Resveratrol inhibits MUC5AC expression by regulating SPDEF in lung cancer cells. Phytomedicine. 2021;89:153601. DOI: https://doi.org/10.1016/j.phymed.2021.153601

9- Behroozaghdam M, Dehghani M, Zabolian A, Kamali D, Javanshir S, Hasani Sadi F, et al. Resveratrol in breast cancer treatment: from cellular effects to molecular mechanisms of action. Cellular and Molecular Life Sciences. 2022;79(11):539. DOI: https://doi.org/10.1007/s00018-022-04551-4

10- Zhang Z, Ji Y, Hu N, Yu Q, Zhang X, Li J, et al. Ferroptosis-induced anticancer effect of resveratrol with a biomimetic nano-delivery system in colorectal cancer treatment. Asian Journal of Pharmaceutical Sciences. 2022;17(5):751-66. DOI: https://doi.org/10.1016/j.ajps.2022.07.006

11- Wang L, Wang Y, Xie Q, Xu S, Yang C, Liu F, et al. Resveratrol liposomes reverse sorafenib resistance in renal cell carcinoma models by modulating PI3K-AKT-mTOR and VHL-HIF signaling pathways. International Journal of Pharmaceutics: X. 2024;8:100280. DOI: https://doi.org/10.1016/j.ijpx.2024.100280

12- Wang Y, Su L, Hu Z, Peng S, Li N, Fu H, et al. Resveratrol suppresses liver cancer progression by downregulating AKR1C3: targeting HCC with HSA nanomaterial as a carrier to enhance therapeutic efficacy. Apoptosis. 2024;29(9):1429-53. DOI: https://doi.org/10.1007/s10495-024-01995-w

13- Khan K, Quispe C, Javed Z, Iqbal MJ, Sadia H, Raza S, et al. Resveratrol, curcumin, paclitaxel and miRNAs mediated regulation of PI3K/Akt/mTOR pathway: go four better to treat bladder cancer. Cancer Cell International. 2020;20(1):560. DOI: https://doi.org/10.1186/s12935-020-01660-7

14- Dun J, Chen X, Gao H, Zhang Y, Zhang H, Zhang Y. Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis. Experimental Biology and Medicine. 2015;240(12):1672-81. DOI: https://doi.org/10.1177/1535370215573396

15- Cotino-Nájera S, Herrera LA, Domínguez-Gómez G, Díaz-Chávez J. Molecular mechanisms of resveratrol as chemo and radiosensitizer in cancer. Frontiers in Pharmacology. 2023;14:1287505. DOI: https://doi.org/10.3389/fphar.2023.1287505

16- Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, et al. Suppression of c-Myc-induced apoptosis by Ras signalling through PI (3) K and PKB. Nature. 1997;385(6616):544-8. DOI: https://doi.org/10.1038/385544a0

17- Gu Y, Mohammad IS, Liu Z. Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors. Oncology letters. 2020;19(4):2585-94. DOI: https://doi.org/10.3892/ol.2020.11394

18- Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nature Reviews Cancer. 2002;2(7):489-501. DOI: https://doi.org/10.1038/nrc839

19- Dutta P, Sabri N, Li J, Li WX. Role of STAT3 in lung cancer. Jak-stat. 2014;3(4):e999503. DOI: https://doi.org/10.1080/21623996.2014.999503

20- Zeng Q-f, Chen Y-j, Yang J-p, Zheng L-p, Ye X, Xie Y. BUB1B promotes gemcitabine resistance in lung adenocarcinoma and activates the PI3K/AKT signaling pathway. The American Journal of the Medical Sciences. 2025. DOI: https://doi.org/10.1016/j.amjms.2025.08.010

21- Guo H, Hu Z, Yang X, Yuan Z, Gao Y, Chen J, et al. STAT3 inhibition enhances gemcitabine sensitivity in pancreatic cancer by suppressing EMT, immune escape and inducing oxidative stress damage. International immunopharmacology. 2023;123:110709. DOI: https://doi.org/10.1016/j.intimp.2023.110709

22- Hanoon MM, Hummadi YMKAM, Abdullah BH. Synergistic Anticancer Effects of Gemcitabine and Resveratrol on A549 Non-Small Cell Lung Cancer Cell Line. Al-Rafidain Journal of Medical Sciences (ISSN 2789-3219). 2026;10(1):120-6. DOI: https://doi.org/10.54133/ajms.v10i1.2651

23- Al-khfajy WS, Arif IS, Al-sudani BT. Synergistic effect of obeticholic acid and fasting-mimicking on proliferative, migration, and survival signaling in prostate cancer. Pharmacia. 2022;69:579-87. DOI: https://doi.org/10.3897/pharmacia.69.e81452

24- Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. European journal of immunology. 2021;51(12):2708-3145. DOI: https://doi.org/10.1002/eji.202170126

25- Salih AI, Mshimesh BA-R, Al-Sudani BT. Investigating the effect of EX-527 as SIRT1 inhibitor in breast cancer cell line. Al-Rafidain Journal of Medical Sciences (ISSN 2789-3219). 2024;7(1 (Special)):S64-9. DOI: https://doi.org/10.54133/ajms.v7i1(Special).926

26- Talib LJ, Al-Sudani BT, Al-Abbassi MG. Aptamer validation by western blot–an overview. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2020;20(4):122-31. DOI: https://doi.org/10.32947/ajps.v20i4.782

27- Hasan HA, Ali KF, Mehdi WA. Synthesis, characterization, docking study and biological activates of new 3-aminorhodanine derivatives. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2024;24(3):299-310. DOI: https://doi.org/10.32947/ajps.v24i3.1072

28- Hatami E, Nagesh PK, Jaggi M, Chauhan SC, Yallapu MM. Gambogic acid potentiates gemcitabine induced anticancer activity in non-small cell lung cancer. European journal of pharmacology. 2020;888:173486. DOI: https://doi.org/10.1016/j.ejphar.2020.173486

29- Su S-H, Sundhar N, Kuo W-W, Lai S-C, Kuo C-H, Ho T-J, et al. Artemisia argyi extract induces apoptosis in human gemcitabine-resistant lung cancer cells via the PI3K/MAPK signaling pathway. Journal of Ethnopharmacology. 2022;299:115658. DOI: https://doi.org/10.1016/j.jep.2022.115658

30- Ko J-H, Sethi G, Um J-Y, Shanmugam MK, Arfuso F, Kumar AP, et al. The role of resveratrol in cancer therapy. International journal of molecular sciences. 2017;18(12):2589. DOI: https://doi.org/10.3390/ijms18122589

31- Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer research. 2004;24(5A):2783-840.

32- Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB. Chemosensitization of tumors by resveratrol. Annals of the New York Academy of Sciences. 2011;1215(1):150-60. DOI: https://doi.org/10.1111/j.1749-6632.2010.05852.x

33- Mohammed S, Harikumar KB. Role of resveratrol in chemosensitization of cancer. Role of nutraceuticals in cancer chemosensitization: Elsevier; 2018. p. 61-76. DOI: https://doi.org/10.1016/B978-0-12-812373-7.00003-6

34- Wu S, Ren J, Qian W, Gong M, Li J, Qin T, et al. Synergistic effects of resveratrol with gemcitabine in pancreatic cancer chemotherapy by inhibiting the c-Met/PARP1 axis. Journal of Pancreatology. 2024;7(04):267-78. DOI: https://doi.org/10.1097/JP9.0000000000000160

35- Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, et al. Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. International journal of cancer. 2010;127(2):257-68. DOI: https://doi.org/10.1002/ijc.25041

36- Zhou C, Qian W, Ma J, Cheng L, Jiang Z, Yan B, et al. Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP 1. Cell proliferation. 2019;52(1):e12514. DOI: https://doi.org/10.1111/cpr.12514

37- Jiang Z, Chen X, Chen K, Sun L, Gao L, Zhou C, et al. YAP inhibition by resveratrol via activation of AMPK enhances the sensitivity of pancreatic cancer cells to gemcitabine. Nutrients. 2016;8(10):546. DOI: https://doi.org/10.3390/nu8100546

38- Zhu Z, Sun H, Ma G, Wang Z, Li E, Liu Y, et al. Bufalin induces lung cancer cell apoptosis via the inhibition of PI3K/Akt pathway. International journal of molecular sciences. 2012;13(2):2025-35. DOI: https://doi.org/10.3390/ijms13022025

39- Tuya N, Wang Y, Tong L, Gao W, Yu R, Xue L. Trichosanthin enhances the antitumor effect of gemcitabine in non-small cell lung cancer via inhibition of the PI3K/AKT pathway. Experimental and Therapeutic Medicine. 2017;14(6):5767-72. DOI: https://doi.org/10.3892/etm.2017.5286

40- Wang J, Zhang Y, Liu X, Wang J, Li B, Liu Y, et al. Alantolactone enhances gemcitabine sensitivity of lung cancer cells through the reactive oxygen species-mediated endoplasmic reticulum stress and Akt/GSK3β pathway. International journal of molecular medicine. 2019;44(3):1026-38. DOI: https://doi.org/10.3892/ijmm.2019.4268

41- Rasheduzzaman M, Jeong J-K, Park S-Y. Resveratrol sensitizes lung cancer cell to TRAIL by p53 independent and suppression of Akt/NF-κB signaling. Life Sciences. 2018;208:208-20. DOI: https://doi.org/10.1016/j.lfs.2018.07.035

42- Hu S, Li X, Xu R, Ye L, Kong H, Zeng X, et al. The synergistic effect of resveratrol in combination with cisplatin on apoptosis via modulating autophagy in A549 cells. Acta biochimica et biophysica Sinica. 2016;48(6):528-35. DOI: https://doi.org/10.1093/abbs/gmw026

43- Venkatasubbarao K, Peterson L, Zhao S, Hill P, Cao L, Zhou Q, et al. Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer. Molecular cancer. 2013;12(1):104. DOI: https://doi.org/10.1186/1476-4598-12-104

44- Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, et al. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB–regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007;109(6):2293-302. DOI: https://doi.org/10.1182/blood-2006-02-003988