Interleukin-6 Modulation in Ovarian Cancer Necessitates a Targeted Strategy: From the Approved to Emerging Therapies

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Jan 8

PMID 39766086

Authors

Hina Amer

Nirmala C Kampan

Catherine Itsiopoulos

Katie L Flanagan

Clare L Scott

Apriliana E R Kartikasari

Magdalena Plebanski

Affiliations

Soon will be listed here.

Abstract

Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more effective approach is warranted to combat OC. The cytokine Interleukin-6 (IL6) has been implicated in various stages of OC development. High IL6 levels are also correlated with a lower survival rate in OC patients. In this current review, we summarized the pivotal roles of IL6 in OC, including the initiation, development, invasion, metastasis, and drug resistance mechanisms. This article systematically highlights how targeting IL6 improves OC outcomes by altering various cancer processes and reports the ongoing clinical trials that would further shape the IL6-based targeted therapies. This review also suggests how combining IL6-targeted therapies with other therapeutic strategies could further enhance their efficacy to combat OC.

References

Wheler J, Moulder S, Naing A, Janku F, Piha-Paul S, Falchook G . Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway. Oncotarget. 2014; 5(10):3029-38. PMC: 4102789. DOI: 10.18632/oncotarget.1799. View

Selvendiran K, Ahmed S, Dayton A, Kuppusamy M, Rivera B, Kalai T . HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol Ther. 2011; 12(9):837-45. DOI: 10.4161/cbt.12.9.17713. View

Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J . AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015; 7(314):314ra185. PMC: 5279222. DOI: 10.1126/scitranslmed.aac5272. View

Zhang R, Wang T, Lin J . Synergistic Effect of Bazedoxifene and PARP Inhibitor in the Treatment of Ovarian Cancer Regardless of BRCA Mutation. Anticancer Res. 2021; 41(5):2277-2286. DOI: 10.21873/anticanres.15003. View

Aghajanian C, Blessing J, Darcy K, Reid G, DeGeest K, Rubin S . A phase II evaluation of bortezomib in the treatment of recurrent platinum-sensitive ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2009; 115(2):215-20. DOI: 10.1016/j.ygyno.2009.07.023. View

George A, Kaye S, Banerjee S . Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. Nat Rev Clin Oncol. 2016; 14(5):284-296. DOI: 10.1038/nrclinonc.2016.191. View

Rose-John S . IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012; 8(9):1237-47. PMC: 3491447. DOI: 10.7150/ijbs.4989. View

Casper C, Chaturvedi S, Munshi N, Wong R, Qi M, Schaffer M . Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease. Clin Cancer Res. 2015; 21(19):4294-304. DOI: 10.1158/1078-0432.CCR-15-0134. View

Gopinathan G, Milagre C, Pearce O, Reynolds L, Hodivala-Dilke K, Leinster D . Interleukin-6 Stimulates Defective Angiogenesis. Cancer Res. 2015; 75(15):3098-107. PMC: 4527186. DOI: 10.1158/0008-5472.CAN-15-1227. View

10.

Masuda K, Kishimoto T . A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression. Curr Pharm Des. 2018; 24(16):1766-1771. DOI: 10.2174/1381612824666180426103753. View

11.

Miletti-Gonzalez K, Chen S, Muthukumaran N, Saglimbeni G, Wu X, Yang J . The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 2005; 65(15):6660-7. DOI: 10.1158/0008-5472.CAN-04-3478. View

12.

Chow M, Luster A . Chemokines in cancer. Cancer Immunol Res. 2014; 2(12):1125-31. PMC: 4258879. DOI: 10.1158/2326-6066.CIR-14-0160. View

13.

Slabakova E, Culig Z, Remsik J, Soucek K . Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis. 2017; 8(10):e3100. PMC: 5682661. DOI: 10.1038/cddis.2017.495. View

14.

Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M . Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005; 5(12):1731-40. DOI: 10.1016/j.intimp.2005.05.010. View

15.

Xu S, Neamati N . gp130: a promising drug target for cancer therapy. Expert Opin Ther Targets. 2013; 17(11):1303-28. DOI: 10.1517/14728222.2013.830105. View

16.

Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K . Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood. 2009; 114(5):1046-52. PMC: 2721785. DOI: 10.1182/blood-2009-01-199604. View

17.

Berek J, Renz M, Kehoe S, Kumar L, Friedlander M . Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet. 2021; 155 Suppl 1:61-85. PMC: 9298325. DOI: 10.1002/ijgo.13878. View

18.

Garcia-Tunon I, Ricote M, Ruiz A, Fraile B, Paniagua R, Royuela M . IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005; 47(1):82-9. DOI: 10.1111/j.1365-2559.2005.02178.x. View

19.

Motamedi H, Mahdizade Ari M, Alvandi A, Abiri R . Principle, application and challenges of development siRNA-based therapeutics against bacterial and viral infections: a comprehensive review. Front Microbiol. 2024; 15:1393646. PMC: 11208694. DOI: 10.3389/fmicb.2024.1393646. View

20.

Becker C, Fantini M, Wirtz S, Nikolaev A, Lehr H, Galle P . IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle. 2005; 4(2):217-20. View