Immunotherapeutic Role of Cabazitaxel Treatment in the Activation of TLR3 Signalling in Metastatic Castration-resistant Prostate Cancer in Vitro

Overview

Journal Mol Biol Rep

Specialty Molecular Biology

Date 2021 Nov 26

PMID 34826050

Citations 3

Authors

Asuman Deveci Ozkan

Gamze Guney Eskiler

Suleyman Kaleli

Elvan Sahin

Affiliations

Soon will be listed here.

Abstract

Background: The activation of toll like receptors (TLR) potentially affect the inflammatory tumor microenvironment and thus is associated with tumor growth or inhibition. Cabazitaxel (CAB) has been effectively used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the immune regulatory role of CAB in the tumor microenvironment is not clear. In this context, we for the first time assessed the immunotherapeutic role of CAB in the TLR3 signalling following activation of Poly I:C in mCRPC cells.

Methods And Results: The cytotoxic and apoptotic effects of CAB with the induction of Poly I:C were determined by WST-1, Annexin V, acridine orange, RT-PCR analysis, ELISA assay and immunofluorescence staining in DU-145 mCRPC and HUVEC control cells. Our findings showed that CAB treatment with Poly I:C significantly suppressed the proliferation of DU-145 cells through the induction of apoptosis and caspase activation. Additionally, higher concentration of CAB mediated the activation of TLR3 via increased cytoplasmic and nuclear expression of TLR3, TICAM-1 and IRF-3 in mCRPC cells.

Conclusions: Co-treatment of CAB and Poly I:C was more effective in mCRPC cells with less toxicity in control cells. However, further investigations are required to elucidate the molecular mechanisms of TLRs signalling upon CAB treatment at the molecular level to further validate the immunotherapeutic efficacy of CAB in mCRPC.

Citing Articles

Natural Compounds and Histone Deacetylase Inhibitors: A Combined Approach Against mCRPC Cells.

Alimudin J, Betts Z, Deveci Ozkan A Biomedicines. 2025; 13(2).

PMID: 40002709 PMC: 11853668. DOI: 10.3390/biomedicines13020296.

Chemotherapeutic properties and side-effects associated with the clinical practice of terpene alkaloids: paclitaxel, docetaxel, and cabazitaxel.

Sousa-Pimenta M, Estevinho L, Szopa A, Basit M, Khan K, Armaghan M Front Pharmacol. 2023; 14:1157306.

PMID: 37229270 PMC: 10203197. DOI: 10.3389/fphar.2023.1157306.

A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells.

de la Torre C, Jativa P, Posadas I, Manzanares D, Jimenez Blanco J, Ortiz Mellet C Pharmaceutics. 2022; 14(11).

PMID: 36365241 PMC: 9692777. DOI: 10.3390/pharmaceutics14112424.

Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening.

Dong H, Li Z, Bian S, Song G, Song W, Zhang M Bioact Mater. 2022; 18:164-177.

PMID: 35387168 PMC: 8961426. DOI: 10.1016/j.bioactmat.2022.03.020.

References

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View

Zhang T, Agarwal N, Sonpavde G, Dilorenzo G, Bellmunt J, Vogelzang N . Management of castrate resistant prostate cancer-recent advances and optimal sequence of treatments. Curr Urol Rep. 2013; 14(3):174-83. DOI: 10.1007/s11934-013-0322-0. View

Yap T, Pezaro C, de Bono J . Cabazitaxel in metastatic castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2012; 12(9):1129-36. DOI: 10.1586/era.12.88. View

Lam J, Leppert J, Vemulapalli S, Shvarts O, Belldegrun A . Secondary hormonal therapy for advanced prostate cancer. J Urol. 2006; 175(1):27-34. DOI: 10.1016/S0022-5347(05)00034-0. View

Tito Fojo A, Menefee M . Microtubule targeting agents: basic mechanisms of multidrug resistance (MDR). Semin Oncol. 2005; 32(6 Suppl 7):S3-8. DOI: 10.1053/j.seminoncol.2005.09.010. View

Galletti G, Matov A, Beltran H, Fontugne J, Mosquera J, Cheung C . ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun. 2014; 5:5548. PMC: 4244604. DOI: 10.1038/ncomms6548. View

de Bono J, Oudard S, Ozguroglu M, Hansen S, Machiels J, Kocak I . Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010; 376(9747):1147-54. DOI: 10.1016/S0140-6736(10)61389-X. View

Dieras V, Lortholary A, Laurence V, Delva R, Girre V, Livartowski A . Cabazitaxel in patients with advanced solid tumours: results of a Phase I and pharmacokinetic study. Eur J Cancer. 2012; 49(1):25-34. DOI: 10.1016/j.ejca.2012.07.008. View

Mita A, Denis L, Rowinsky E, deBono J, Goetz A, Ochoa L . Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009; 15(2):723-30. DOI: 10.1158/1078-0432.CCR-08-0596. View

10.

Vrignaud P, Semiond D, Benning V, Beys E, Bouchard H, Gupta S . Preclinical profile of cabazitaxel. Drug Des Devel Ther. 2014; 8:1851-67. PMC: 4207555. DOI: 10.2147/DDDT.S64940. View

11.

Vrignaud P, Semiond D, Lejeune P, Bouchard H, Calvet L, Combeau C . Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 2013; 19(11):2973-83. DOI: 10.1158/1078-0432.CCR-12-3146. View

12.

Kuo W, Lee T, Yu L . Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide. Cancer Res. 2016; 76(16):4684-95. DOI: 10.1158/0008-5472.CAN-16-0172. View

13.

Prakash H, Nadella V, Singh S, Schmitz-Winnenthal H . CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma. Sci Rep. 2016; 6:31490. PMC: 4980608. DOI: 10.1038/srep31490. View

14.

Llitjos J, Auffray C, Alby-Laurent F, Rousseau C, Merdji H, Bonilla N . Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4. J Pathol. 2016; 239(4):473-83. DOI: 10.1002/path.4744. View

15.

Zhao S, Zhang Y, Zhang Q, Wang F, Zhang D . Toll-like receptors and prostate cancer. Front Immunol. 2014; 5:352. PMC: 4107957. DOI: 10.3389/fimmu.2014.00352. View

16.

Iwasaki A, Medzhitov R . Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004; 5(10):987-95. DOI: 10.1038/ni1112. View

17.

Harashima N, Inao T, Imamura R, Okano S, Suda T, Harada M . Roles of the PI3K/Akt pathway and autophagy in TLR3 signaling-induced apoptosis and growth arrest of human prostate cancer cells. Cancer Immunol Immunother. 2011; 61(5):667-76. PMC: 11029084. DOI: 10.1007/s00262-011-1132-1. View

18.

Braunstein M, Kucharczyk J, Adams S . Targeting Toll-Like Receptors for Cancer Therapy. Target Oncol. 2018; 13(5):583-598. DOI: 10.1007/s11523-018-0589-7. View

19.

Paone A, Starace D, Galli R, Padula F, De Cesaris P, Filippini A . Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism. Carcinogenesis. 2008; 29(7):1334-42. DOI: 10.1093/carcin/bgn149. View

20.

Eskiler G, Deveci Ozkan A, Eryilmaz I, Egeli U, Cecener G . Association between the anticancer efficacy of cabazitaxel and toll-like receptor 4 mediating signaling pathways in metastatic castration-resistant prostate cancer cells. Hum Exp Toxicol. 2020; 40(7):1122-1129. DOI: 10.1177/0960327120984209. View