Exploring Anticancer Potential of Anethum graveolens: Effects on Apoptosis and HER2 Expression in Human Gastric Adenocarcinoma
-
Neda Ahmad Nejad Ahranjani
,
Maryam Farghadan
,
Mehrnoosh Pashaei
,
Sepideh Ashouri Movassagh
,
Seyed Abolhassan Shahzadeh Fazeli
Abstract
Gastric cancer is among the most prevalent malignancies worldwide, with a poor prognosis in advanced stages. Overexpression of human epidermal growth factor receptor 2 (HER2, also known as ERBB2) and heat shock protein 90 alpha (HSP90AA1, also known as HSP90α) has been associated with tumor progression. Anethum graveolens, a medicinal plant from the Apiaceae family, has demonstrated anticancer properties in previous studies. This study aimed to evaluate the effects of A graveolens methanolic extract on apoptosis and the expression of HER2, HSP90α, tumor protein p53 (TP53), and caspase-3 genes in the human gastric adenocarcinoma cell line (AGS).
A methanolic extract of the aerial parts of A graveolens was prepared. Cytotoxicity was assessed in AGS and human gingival fibroblast (HUGU) cell lines using the -(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Gene expression was measured by real-time PCR, and apoptosis was evaluated using Annexin V/propidium iodide (PI) staining followed by flow cytometry.
The methanolic extract exhibited dose-dependent cytotoxicity, with a half-maximal inhibitory concentration (IC50) of 1280 μg/mL in AGS cells. Gene expression analysis revealed significant downregulation of HER2 and upregulation of HSP90α, TP53, and caspase-3 in treated AGS cells compared to controls. Apoptosis rates were significantly higher in treated AGS cells, confirming the proapoptotic effect of the extract. A graveolens exerts cytotoxic and proapoptotic effects in AGS cells and modulates key genes involved in gastric cancer progression.
These findings suggest its potential as a natural therapeutic candidate for gastric cancer, warranting further preclinical and clinical investigations.
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4. Broekgaarden M, Weijer R, van Gulik TM, Hamblin MR, Heger M. Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev. 2015;34:643-90.
5. Chaudhry GeS, Md Akim A, Sung YY, Sifzizul TMT. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Front Pharmacol. 2022;13:842376.
6. Lordick F, Rha SY, Muro K, Yong WP, Lordick Obermannová R. Systemic therapy of gastric cancer—state of the art and future perspectives. Cancers. 2024;16(19):3337.
7. Kaur GJ, Arora DS. Bioactive potential of Anethum graveolens, Foeniculum vulgare and Trachyspermum ammi belonging to the family Umbelliferae-Current status. J Med Plants Res. 2010;4(2):087-94.
8. Ahmed SST, Fahim J, Abdelmohsen UR. Chemical and biological potential of Ammi visnaga (L.) Lam. and Apium graveolens L.: a review (1963-2020). J Adv Biomed Pharm Sci. 2021;4(3):160-76.
9. Wang XJ, Luo Q, Li T, Meng PH, Pu YT, Liu JX, et al. Origin, evolution, breeding, and omics of Apiaceae: a family of vegetables and medicinal plants. Hortic Res. 2022;9:uhac076.
10. Kazemi M. Chemical composition and antimicrobial, antioxidant activities and anti-inflammatory potential of Achillea millefolium L., Anethum graveolens L., and Carum copticum L. essential oils. J Herb Med. 2015;5(4):217-22.
11. Al-Oqail MM, Farshori NN. Antioxidant and anticancer efficacies of anethum graveolens against human breast carcinoma cells through oxidative stress and caspase dependency. Biomed Res Int. 2021;2021(1):5535570.
12. Nehdia I, Abutaha N, Sbihi H, Tan C, Al-Resayes S. Chemical composition, oxidative stability and antiproliferative activity of Anethum graveolens (dill) seed hexane extract. Grasas Aceites. 2020;71(3):e374-e.
13. Moser C, Lang SA, Stoeltzing O. Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer. Anticancer Res. 2009;29(6):2031-42.
14. Grávalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523-9.
15. Liang Xq, Li Kz, Li Z, Xie Mz, Tang Yp, Du Jb, et al. Diagnostic and prognostic value of plasma heat shock protein 90alpha in gastric cancer. Int Immunopharmacol. 2021;90:107145.
16. Plum PS, Gebauer F, Krämer M, Alakus H, Berlth F, Chon SH, et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer. 2019;19:1-9.
17. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol. 2016;22(19):4619.
18. Pous A, Notario L, Hierro C, Layos L, Bugés C. HER2-positive gastric cancer: the role of immunotherapy and novel therapeutic strategies. Int J Mol Sci. 2023;24(14):11403.
19. Kumar R, George B, Campbell MR, Verma N, Paul AM, Melo-Alvim C, et al. HER family in cancer progression: From discovery to 2020 and beyond. Adv Cancer Res. 2020;147:109-60.
20. Lee H, Kim K. Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer. Niger J Clin Pract. 2019;22(12):1698-705.
21. Slotta-Huspenina J, Becker KF, Feith M, Walch A, Langer R. Heat shock protein 90 (HSP90) and Her2 in adenocarcinomas of the esophagus. Cancers. 2014;6(3):1382-93.
22. Qadir Z, Crown J, Jensen M, Clynes M, Slamon D, O’Donovan N. HSP90 inhibition in HER2-positive breast cancer cells. J Clin Oncol. 2009;27(15_suppl):e14573-e.
23. Jan R. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019;9(2):205.
24. Pfeffer CM, Singh AT. Apoptosis: a target for anticancer therapy. Int J Mol Sci. 2018;19(2):448.
25. Mustafa M, Ahmad R, Tantry IQ, Ahmad W, Siddiqui S, Alam M, et al. Apoptosis: a comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells. 2024;13(22):1838.
26. Qian Se, Long Y, Tan G, Li X, Xiang B, Tao Y, et al. Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets. MedComm. 2024;5(12):e70024.
27. Plati J, Bucur O, Khosravi‐Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008;104(4):1124-49.
28. Helton ES, Chen X. p53 modulation of the DNA damage response. J Cell Biochem. 2007;100(4):883-96.
29. Vousden KH. Functions of p53 in metabolism and invasion. Biochem Soc Trans. 2009;37(3):511-7.
30. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8(4):275-83.
31. Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6(5):a026062.
32. Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159.
33. Park JY, Von Karsa L, Herrero R. Prevention strategies for gastric cancer: a global perspective. Clin Endosc. 2014;47(6):478-89.
34. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21(11):4012.
35. Zhang B, Deng Z, Ramdath DD, Tang Y, Chen PX, Liu R, et al. Phenolic profiles of 20 Canadian lentil cultivars and their contribution to antioxidant activity and inhibitory effects on α-glucosidase and pancreatic lipase. Food Chem. 2015;172:862-72.
36. Hossen MJ, Cho JY, Kim D. PDK1 in NF-κB signaling is a target of Xanthium strumarium methanolic extract-mediated anti-inflammatory activities. J Ethnopharmacol. 2016;190:251-60.
37. Mohammed FA, Elkady AI, Syed FQ, Mirza MB, Hakeem KR, Alkarim S. Anethum graveolens (dill)–A medicinal herb induces apoptosis and cell cycle arrest in HepG2 cell line. J Ethnopharmacol. 2018;219:15-22.
38. Khan I, Peng J, Fang Z, Liu W, Zhang W, Zhang Q, et al. Cylindromicin from arctic-derived fungus Tolypocladium sp. SCSIO 40433. Molecules. 2021;26(4):1080.
39. Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE. Potential antiparkinsonian agents derived from South African medicinal plants. J Herb Med. 2018;13:1-7.
40. Bortolin RC, Vargas AR, de Miranda Ramos V, Gasparotto J, Chaves PR, Schnorr CE, et al. Guarana supplementation attenuated obesity, insulin resistance, and adipokines dysregulation induced by a standardized human Western diet via brown adipose tissue activation. Phytother Res. 2019;33(5):1394-403.
41. Lima Tolouei SE, Palozi RAC, Tirloni CAS, Marques AAM, Schaedler MI, Guarnier LP, et al. Anchietea pyrifolia A. St.-Hil. as a cardiovascular-endowed species: a whole-biological investigation. J Med Food. 2019;22(4):393-407.
42. Gupta S, Prem R, Sethy C, Shrivastava S, Singh M, Yadav P, et al. Exploring anticancer properties of medicinal plants against breast cancer by downregulating human epidermal growth factor receptor 2. J Agric Food Chem. 2024;72(17):9717-34.
43. Jahanban-Esfahlan R, Seidi K, Monfaredan A, Shafie-Irannejad V, Abbasi MM, Karimian A, et al. The herbal medicine Melissa officinalis extract effects on gene expression of p53, Bcl-2, Her2, VEGF-A and hTERT in human lung, breast and prostate cancer cell lines. Gene. 2017;613:14-9.
44. Ray A, Gadnayak A, Jena S, Sahoo A, Patnaik J, Panda PC, et al. Hedychium spicatum rhizome essential oil induces apoptosis in human prostate adenocarcinoma PC-3 cells via mitochondrial stress and caspase activation. Heliyon. 2023;9(3).
45. Nam GH, Jo KJ, Park YS, Kawk HW, Kim SY, Kim YM. In vitro and in vivo induction of p53-dependent apoptosis by extract of Euryale ferox Salisb in A549 human Caucasian lung carcinoma cancer cells is mediated through Akt signaling pathway. Front Oncol. 2019;9:406.
46. Fouzat A, Hussein OJ, Gupta I, Al-Farsi HF, Khalil A, Al Moustafa AE. Elaeagnus angustifolia plant extract induces apoptosis via P53 and signal transducer and activator of transcription 3 signaling pathways in triple-negative breast cancer cells. Front Nutr. 2022;9:871667.
2. Forough H, Haghighi G, Ganjali A. Mechanisms involved in the progression of Gastric cancer caused by Helicobacter pylori. Navid No. 2023;25(84):82-92.
3. Gholami M, Elyasigorji Z, Amoli AD, Farzaneh P. Effects of Alkanna bracteosa extract on the expression level of HSP90α and HER2 genes in human gastric cancer cell line. Adv Tradit Med. 2023;23(3):877-86.
4. Broekgaarden M, Weijer R, van Gulik TM, Hamblin MR, Heger M. Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies. Cancer Metastasis Rev. 2015;34:643-90.
5. Chaudhry GeS, Md Akim A, Sung YY, Sifzizul TMT. Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Front Pharmacol. 2022;13:842376.
6. Lordick F, Rha SY, Muro K, Yong WP, Lordick Obermannová R. Systemic therapy of gastric cancer—state of the art and future perspectives. Cancers. 2024;16(19):3337.
7. Kaur GJ, Arora DS. Bioactive potential of Anethum graveolens, Foeniculum vulgare and Trachyspermum ammi belonging to the family Umbelliferae-Current status. J Med Plants Res. 2010;4(2):087-94.
8. Ahmed SST, Fahim J, Abdelmohsen UR. Chemical and biological potential of Ammi visnaga (L.) Lam. and Apium graveolens L.: a review (1963-2020). J Adv Biomed Pharm Sci. 2021;4(3):160-76.
9. Wang XJ, Luo Q, Li T, Meng PH, Pu YT, Liu JX, et al. Origin, evolution, breeding, and omics of Apiaceae: a family of vegetables and medicinal plants. Hortic Res. 2022;9:uhac076.
10. Kazemi M. Chemical composition and antimicrobial, antioxidant activities and anti-inflammatory potential of Achillea millefolium L., Anethum graveolens L., and Carum copticum L. essential oils. J Herb Med. 2015;5(4):217-22.
11. Al-Oqail MM, Farshori NN. Antioxidant and anticancer efficacies of anethum graveolens against human breast carcinoma cells through oxidative stress and caspase dependency. Biomed Res Int. 2021;2021(1):5535570.
12. Nehdia I, Abutaha N, Sbihi H, Tan C, Al-Resayes S. Chemical composition, oxidative stability and antiproliferative activity of Anethum graveolens (dill) seed hexane extract. Grasas Aceites. 2020;71(3):e374-e.
13. Moser C, Lang SA, Stoeltzing O. Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer. Anticancer Res. 2009;29(6):2031-42.
14. Grávalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523-9.
15. Liang Xq, Li Kz, Li Z, Xie Mz, Tang Yp, Du Jb, et al. Diagnostic and prognostic value of plasma heat shock protein 90alpha in gastric cancer. Int Immunopharmacol. 2021;90:107145.
16. Plum PS, Gebauer F, Krämer M, Alakus H, Berlth F, Chon SH, et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer. 2019;19:1-9.
17. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol. 2016;22(19):4619.
18. Pous A, Notario L, Hierro C, Layos L, Bugés C. HER2-positive gastric cancer: the role of immunotherapy and novel therapeutic strategies. Int J Mol Sci. 2023;24(14):11403.
19. Kumar R, George B, Campbell MR, Verma N, Paul AM, Melo-Alvim C, et al. HER family in cancer progression: From discovery to 2020 and beyond. Adv Cancer Res. 2020;147:109-60.
20. Lee H, Kim K. Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer. Niger J Clin Pract. 2019;22(12):1698-705.
21. Slotta-Huspenina J, Becker KF, Feith M, Walch A, Langer R. Heat shock protein 90 (HSP90) and Her2 in adenocarcinomas of the esophagus. Cancers. 2014;6(3):1382-93.
22. Qadir Z, Crown J, Jensen M, Clynes M, Slamon D, O’Donovan N. HSP90 inhibition in HER2-positive breast cancer cells. J Clin Oncol. 2009;27(15_suppl):e14573-e.
23. Jan R. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019;9(2):205.
24. Pfeffer CM, Singh AT. Apoptosis: a target for anticancer therapy. Int J Mol Sci. 2018;19(2):448.
25. Mustafa M, Ahmad R, Tantry IQ, Ahmad W, Siddiqui S, Alam M, et al. Apoptosis: a comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells. 2024;13(22):1838.
26. Qian Se, Long Y, Tan G, Li X, Xiang B, Tao Y, et al. Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets. MedComm. 2024;5(12):e70024.
27. Plati J, Bucur O, Khosravi‐Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008;104(4):1124-49.
28. Helton ES, Chen X. p53 modulation of the DNA damage response. J Cell Biochem. 2007;100(4):883-96.
29. Vousden KH. Functions of p53 in metabolism and invasion. Biochem Soc Trans. 2009;37(3):511-7.
30. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8(4):275-83.
31. Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med. 2016;6(5):a026062.
32. Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159.
33. Park JY, Von Karsa L, Herrero R. Prevention strategies for gastric cancer: a global perspective. Clin Endosc. 2014;47(6):478-89.
34. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21(11):4012.
35. Zhang B, Deng Z, Ramdath DD, Tang Y, Chen PX, Liu R, et al. Phenolic profiles of 20 Canadian lentil cultivars and their contribution to antioxidant activity and inhibitory effects on α-glucosidase and pancreatic lipase. Food Chem. 2015;172:862-72.
36. Hossen MJ, Cho JY, Kim D. PDK1 in NF-κB signaling is a target of Xanthium strumarium methanolic extract-mediated anti-inflammatory activities. J Ethnopharmacol. 2016;190:251-60.
37. Mohammed FA, Elkady AI, Syed FQ, Mirza MB, Hakeem KR, Alkarim S. Anethum graveolens (dill)–A medicinal herb induces apoptosis and cell cycle arrest in HepG2 cell line. J Ethnopharmacol. 2018;219:15-22.
38. Khan I, Peng J, Fang Z, Liu W, Zhang W, Zhang Q, et al. Cylindromicin from arctic-derived fungus Tolypocladium sp. SCSIO 40433. Molecules. 2021;26(4):1080.
39. Enogieru AB, Omoruyi SI, Hiss DC, Ekpo OE. Potential antiparkinsonian agents derived from South African medicinal plants. J Herb Med. 2018;13:1-7.
40. Bortolin RC, Vargas AR, de Miranda Ramos V, Gasparotto J, Chaves PR, Schnorr CE, et al. Guarana supplementation attenuated obesity, insulin resistance, and adipokines dysregulation induced by a standardized human Western diet via brown adipose tissue activation. Phytother Res. 2019;33(5):1394-403.
41. Lima Tolouei SE, Palozi RAC, Tirloni CAS, Marques AAM, Schaedler MI, Guarnier LP, et al. Anchietea pyrifolia A. St.-Hil. as a cardiovascular-endowed species: a whole-biological investigation. J Med Food. 2019;22(4):393-407.
42. Gupta S, Prem R, Sethy C, Shrivastava S, Singh M, Yadav P, et al. Exploring anticancer properties of medicinal plants against breast cancer by downregulating human epidermal growth factor receptor 2. J Agric Food Chem. 2024;72(17):9717-34.
43. Jahanban-Esfahlan R, Seidi K, Monfaredan A, Shafie-Irannejad V, Abbasi MM, Karimian A, et al. The herbal medicine Melissa officinalis extract effects on gene expression of p53, Bcl-2, Her2, VEGF-A and hTERT in human lung, breast and prostate cancer cell lines. Gene. 2017;613:14-9.
44. Ray A, Gadnayak A, Jena S, Sahoo A, Patnaik J, Panda PC, et al. Hedychium spicatum rhizome essential oil induces apoptosis in human prostate adenocarcinoma PC-3 cells via mitochondrial stress and caspase activation. Heliyon. 2023;9(3).
45. Nam GH, Jo KJ, Park YS, Kawk HW, Kim SY, Kim YM. In vitro and in vivo induction of p53-dependent apoptosis by extract of Euryale ferox Salisb in A549 human Caucasian lung carcinoma cancer cells is mediated through Akt signaling pathway. Front Oncol. 2019;9:406.
46. Fouzat A, Hussein OJ, Gupta I, Al-Farsi HF, Khalil A, Al Moustafa AE. Elaeagnus angustifolia plant extract induces apoptosis via P53 and signal transducer and activator of transcription 3 signaling pathways in triple-negative breast cancer cells. Front Nutr. 2022;9:871667.
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How to Cite
1.
Ahmad Nejad Ahranjani N, Farghadan M, Pashaei M, Ashouri Movassagh S, Shahzadeh Fazeli SA. Exploring Anticancer Potential of Anethum graveolens: Effects on Apoptosis and HER2 Expression in Human Gastric Adenocarcinoma. Iran J Allergy Asthma Immunol. 2026;:1-11.
