Research Article
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Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer

Year 2023, Volume: 25 Issue: 3, 225 - 230, 30.12.2023
https://doi.org/10.18678/dtfd.1315416

Abstract

Aim: In this study, the effects of muscarinic acetylcholine receptor (mAChR) agonist carbachol on the proliferation of cisplatin-resistant (A2780cis) and cisplatin-free (SKOV-3) ovarian cancer cell line were for the first time investigated to further evaluate the potential therapeutic effect of metronomic chemotherapy.
Material and Methods: The inhibitory effect of carbachol on cell proliferation was detected using the xCELLigence Real-Time Cell Analyzer (RTCA) dual plate (DP) system. A preliminary study was conducted to determine the dose of carbachol 100 µM, cisplatin 1 µM, and two combination studies were carried out with 100 µM carbachol + cisplatin 1 µM and 100 µM carbachol + 10 µM atropine, over cancer cells without drugs was used as the control group. The cell proliferation curve was monitored for 96 hours. The cell index value of inhibition in cell proliferation was automatically measured every hour for each well using RTCA 1.2.1 software.
Results: Co-administration of carbachol with cisplatin caused a decrease in cell number in both A2780cis and SKOV-3 cell lines in a time-dependent manner (p<0.001). Substantial cell death was observed in both cisplatin-resistant (A2780cis) and cisplatin-free (SKOV-3) cell lines within 24 hours after carbachol with cisplatin application and this continued at the 96th hour.
Conclusion: The findings of this study confirm the notion that mAChRs can be considered as therapeutic targets for metronomic therapy in ovarian cancer, as well as the usefulness of a muscarinic agonist as a repositioning drug in the treatment of such tumors.

Thanks

The authors thank Mersin University Advanced Technology Education Research and Application Center.

References

  • Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7(2):79-94.
  • Zhang Q, Madden NE, Wong AST, Chow BKC, Lee LTO. The Role of endocrine G protein-coupled receptors in ovarian cancer progression. Front Endocrinol (Lausanne). 2017;8:66.
  • Gutkind JS, Novotny EA, Brann MR, Robbins KC. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci USA. 1991;88(1):4703-7.
  • Español AJ, Jacob G, Dmytrenko G, Sales ME. Muscarinic activation enhances the anti-proliferative effect of paclitaxel in murine breast tumor cells. Anticancer Agents Med Chem. 2013;13(8):1273-9.
  • Aydın B, Tulunay A, Ekşioğlu-Demiralp E, Kan B, Cabadak H. Effects of carbachol on apoptosis in human chronic myelogenous leukemic K562 cell line. Marmara Med J. 2019;32(1):38-43.
  • Salem AR, Martínez Pulido P, Sanchez F, Sanchez Y, Rojo D, Español AJ. Effect of low dose metronomic therapy on MCF-7 tumor cells growth and angiogenesis. Role of muscarinic acetylcholine receptors. Int Immunopharmacol. 2020;84:106514. Corrigendum. Int Immunopharmacol. 2020;85:106701.
  • Uçar T, Güney E, Bal Z. Psychosocial aspects of gynecologic cancer. Sakarya Med J. 2018;8(4):678-85.
  • Cannistra SA. Cancer of the ovary. N Eng J Med. 2004;351(24):2519-29.
  • Oppitz M, Mobus V, Brock S, Drews U. Muscarinic receptors in cell lines from ovarian carcinoma: negative correlation with survival of patients. Gynecol Oncol. 2002;85(1):159-64.
  • Batra S, Popper LD, Iosif CS. Characterization of muscarinic cholinergic receptors in human ovaries, ovarian tumours and tumour cell lines. Eur J Cancer. 1993;29A(9):1302-6.
  • Popper L, Batra S. Muscarinic acetylcholine and histamine-receptor mediated calcium mobilization and cell-growth in human ovarian-cancer cells. Int J Oncol. 1994;4(2):453-9.
  • Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105(8):1045-7.
  • Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12(11):631-44.
  • Kamat AA, Kim TJ, Landen CN Jr, Lu C, Han LY, Lin YG, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res. 2007;67(1):281-8.
  • Su WH, Ho TY, Li YT, Lu CH, Lee WL, Wang PH. Metronomic therapy for gynecologic cancers. Taiwan J Obstet Gynecol. 2012;51(2):167-78.
  • Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423-36.
  • Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, et al. Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol Cancer Ther. 2010;9(4):996-1006.
  • Merritt WM, Nick AM, Carroll AR, Lu C, Matsuo K, Dumble M, et al. Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer. Mol Cancer Ther. 2010;9(4):985-95.
  • Español AJ, Salem A, Di Bari M, Cristofaro I, Sanchez Y, Tata AM, et al. The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation ofM2 receptor subtype. PLoS One. 2020;15(9):e0226450.

Yumurtalık Kanserinde Metronomik Tedavi Hedefi Olarak Muskarinik Reseptörler

Year 2023, Volume: 25 Issue: 3, 225 - 230, 30.12.2023
https://doi.org/10.18678/dtfd.1315416

Abstract

Amaç: Bu çalışmada, muskarinik asetilkolin reseptörü (mAChR) agonisti karbakolun, sisplatine dirençli (A2780cis) ve sisplatine dirençsiz (SKOV-3) yumurtalık kanseri hücre hatlarının proliferasyonu üzerindeki etkileri, metronomik kemoterapinin potansiyel terapötik etkisini daha ileri düzeyde değerlendirmek üzere ilk kez araştırıldı.
Gereç ve Yöntemler: Karbakolün hücre proliferasyonu üzerindeki inhibitör etkisi, xCELLigence Real-Time Cell Analyzer (RTCA) dual plate (DP) sistemi kullanılarak tespit edildi. 100 µM karbakol ve 1 µM sisplatin dozunu belirlemek için bir ön çalışma yapıldı ve 100 µM karbakol + 1 µM sisplatin ve 100 µM karbakol + 10 µM atropin olmak üzere iki kombinasyon çalışması yapıldı, ilaçsız yumurtalık kanser hücreleri ise kontrol grubu olarak kullanıldı. Hücre proliferasyon eğrisi 96 saat izlendi. Hücre proliferasyonundaki inhibisyonun hücre indeksi değeri, RTCA 1.2.1 yazılımı ile her kuyu için her saat otomatik olarak ölçüldü.
Bulgular: Karbakolun sisplatin ile birlikte uygulanması hem A2780cis hem de SKOV-3 hücre hatlarında zamana bağlı olarak hücre sayısında azalmaya neden olmuştur (p<0.001). Sisplatin ile karbakol uygulamasından sonraki 24 saat içinde sisplatine dirençli (A2780cis) ve sisplatine dirençsiz (SKOV-3) her iki hücre hattında da önemli düzeyde hücre ölümü gözlenmiş ve bu durum 96. saatte de devam etmiştir (p<0.001).
Sonuç: Bu çalışmanın bulguları, mAChR'lerin yumurtalık kanserinde metronomik tedavi için terapötik hedefler olarak kabul edilebileceği fikrini ve ayrıca bu tür tümörlerin tedavisinde bir muskarinik agonistin bir yeniden konumlandırma ilacı olarak kullanışlılığını doğrulamaktadır.

References

  • Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7(2):79-94.
  • Zhang Q, Madden NE, Wong AST, Chow BKC, Lee LTO. The Role of endocrine G protein-coupled receptors in ovarian cancer progression. Front Endocrinol (Lausanne). 2017;8:66.
  • Gutkind JS, Novotny EA, Brann MR, Robbins KC. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci USA. 1991;88(1):4703-7.
  • Español AJ, Jacob G, Dmytrenko G, Sales ME. Muscarinic activation enhances the anti-proliferative effect of paclitaxel in murine breast tumor cells. Anticancer Agents Med Chem. 2013;13(8):1273-9.
  • Aydın B, Tulunay A, Ekşioğlu-Demiralp E, Kan B, Cabadak H. Effects of carbachol on apoptosis in human chronic myelogenous leukemic K562 cell line. Marmara Med J. 2019;32(1):38-43.
  • Salem AR, Martínez Pulido P, Sanchez F, Sanchez Y, Rojo D, Español AJ. Effect of low dose metronomic therapy on MCF-7 tumor cells growth and angiogenesis. Role of muscarinic acetylcholine receptors. Int Immunopharmacol. 2020;84:106514. Corrigendum. Int Immunopharmacol. 2020;85:106701.
  • Uçar T, Güney E, Bal Z. Psychosocial aspects of gynecologic cancer. Sakarya Med J. 2018;8(4):678-85.
  • Cannistra SA. Cancer of the ovary. N Eng J Med. 2004;351(24):2519-29.
  • Oppitz M, Mobus V, Brock S, Drews U. Muscarinic receptors in cell lines from ovarian carcinoma: negative correlation with survival of patients. Gynecol Oncol. 2002;85(1):159-64.
  • Batra S, Popper LD, Iosif CS. Characterization of muscarinic cholinergic receptors in human ovaries, ovarian tumours and tumour cell lines. Eur J Cancer. 1993;29A(9):1302-6.
  • Popper L, Batra S. Muscarinic acetylcholine and histamine-receptor mediated calcium mobilization and cell-growth in human ovarian-cancer cells. Int J Oncol. 1994;4(2):453-9.
  • Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105(8):1045-7.
  • Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12(11):631-44.
  • Kamat AA, Kim TJ, Landen CN Jr, Lu C, Han LY, Lin YG, et al. Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res. 2007;67(1):281-8.
  • Su WH, Ho TY, Li YT, Lu CH, Lee WL, Wang PH. Metronomic therapy for gynecologic cancers. Taiwan J Obstet Gynecol. 2012;51(2):167-78.
  • Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423-36.
  • Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, et al. Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol Cancer Ther. 2010;9(4):996-1006.
  • Merritt WM, Nick AM, Carroll AR, Lu C, Matsuo K, Dumble M, et al. Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer. Mol Cancer Ther. 2010;9(4):985-95.
  • Español AJ, Salem A, Di Bari M, Cristofaro I, Sanchez Y, Tata AM, et al. The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation ofM2 receptor subtype. PLoS One. 2020;15(9):e0226450.
There are 19 citations in total.

Details

Primary Language English
Subjects Cancer Cell Biology
Journal Section Research Article
Authors

Fatma Söylemez 0000-0002-1939-8691

Çağatay Han Türkseven 0000-0002-0584-0661

Early Pub Date October 23, 2023
Publication Date December 30, 2023
Submission Date June 15, 2023
Published in Issue Year 2023 Volume: 25 Issue: 3

Cite

APA Söylemez, F., & Türkseven, Ç. H. (2023). Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer. Duzce Medical Journal, 25(3), 225-230. https://doi.org/10.18678/dtfd.1315416
AMA Söylemez F, Türkseven ÇH. Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer. Duzce Med J. December 2023;25(3):225-230. doi:10.18678/dtfd.1315416
Chicago Söylemez, Fatma, and Çağatay Han Türkseven. “Muscarinic Receptors As Targets for Metronomic Therapy in Ovarian Cancer”. Duzce Medical Journal 25, no. 3 (December 2023): 225-30. https://doi.org/10.18678/dtfd.1315416.
EndNote Söylemez F, Türkseven ÇH (December 1, 2023) Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer. Duzce Medical Journal 25 3 225–230.
IEEE F. Söylemez and Ç. H. Türkseven, “Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer”, Duzce Med J, vol. 25, no. 3, pp. 225–230, 2023, doi: 10.18678/dtfd.1315416.
ISNAD Söylemez, Fatma - Türkseven, Çağatay Han. “Muscarinic Receptors As Targets for Metronomic Therapy in Ovarian Cancer”. Duzce Medical Journal 25/3 (December 2023), 225-230. https://doi.org/10.18678/dtfd.1315416.
JAMA Söylemez F, Türkseven ÇH. Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer. Duzce Med J. 2023;25:225–230.
MLA Söylemez, Fatma and Çağatay Han Türkseven. “Muscarinic Receptors As Targets for Metronomic Therapy in Ovarian Cancer”. Duzce Medical Journal, vol. 25, no. 3, 2023, pp. 225-30, doi:10.18678/dtfd.1315416.
Vancouver Söylemez F, Türkseven ÇH. Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer. Duzce Med J. 2023;25(3):225-30.