Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Line, Drug Preparation, and Cytotoxicity Assay
2.2. Colony Formation Assay
2.3. Therapeutic Evaluation of the Combinational Treatment of Curcumin and Radiotherapy in a Bilateral Tumor-Bearing Mouse Model
2.4. Flow Cytometry—Frequencies of CD4+ and CD8+ T Cells
2.5. Radiolabeling of Indium-111 Anti-OX40 mAb
2.6. Biodistribution of 111In-DOTA-Anti-OX40 mAb
2.7. Western Blot
2.8. ELISA
2.9. Statistics
3. Results
3.1. Curcumin Shows the Potential for Immunomodulation
3.2. Curcumin Enhances the Therapeutic Efficacy of Radiotherapy and Augments the Radiotherapy-Induced Abscopal Effect in Bilateral CT26 Tumor-Bearing Mice
3.3. Biodistribution of 111In-DOTA-Anti-OX40 mAb Reveals That the Combination Treatment Led to Higher Activated T Cell Accumulation in the Primary and Secondary Tumors
3.4. Combination Treatment Upregulates Proinflammatory, Proapoptosis-Associated Protein Levels and Elevates the Concentrations of Proinflammatory Cytokines in Tumors
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
- McLaughlin, M.; Patin, E.C.; Pedersen, M.; Wilkins, A.; Dillon, M.T.; Melcher, A.A.; Harrington, K.J. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat. Rev. Cancer 2020, 20, 203–217. [Google Scholar] [CrossRef] [PubMed]
- Demaria, S.; Ng, B.; Devitt, M.L.; Babb, J.S.; Kawashima, N.; Liebes, L.; Formenti, S.C. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 2004, 58, 862–870. [Google Scholar] [CrossRef] [PubMed]
- Strigari, L.; Mancuso, M.; Ubertini, V.; Soriani, A.; Giardullo, P.; Benassi, M.; D’Alessio, D.; Leonardi, S.; Soddu, S.; Bossi, G. Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status. Int. J. Radiat. Biol. 2014, 90, 248–255. [Google Scholar] [CrossRef] [PubMed]
- Takenaka, W.; Takahashi, Y.; Tamari, K.; Minami, K.; Katsuki, S.; Seo, Y.; Isohashi, F.; Koizumi, M.; Ogawa, K. Radiation Dose Escalation is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance Local and Distant Antitumor Effect in Murine Osteosarcoma. Cancers 2020, 12, 1546. [Google Scholar] [CrossRef] [PubMed]
- Azad, A.; Yin Lim, S.; D’Costa, Z.; Jones, K.; Diana, A.; Sansom, O.J.; Kruger, P.; Liu, S.; McKenna, W.G.; Dushek, O.; et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol. Med. 2017, 9, 167–180. [Google Scholar] [CrossRef]
- Helm, A.; Tinganelli, W.; Simoniello, P.; Kurosawa, F.; Fournier, C.; Shimokawa, T.; Durante, M. Reduction of Lung Metastases in a Mouse Osteosarcoma Model Treated With Carbon Ions and Immune Checkpoint Inhibitors. Int. J. Radiat. Oncol. Biol. Phys. 2021, 109, 594–602. [Google Scholar] [CrossRef]
- Sonveaux, P.; Brouet, A.; Havaux, X.; Grégoire, V.; Dessy, C.; Balligand, J.L.; Feron, O. Irradiation-induced angiogenesis through the up-regulation of the nitric oxide pathway: Implications for tumor radiotherapy. Cancer Res. 2003, 63, 1012–1019. [Google Scholar]
- Teresa Pinto, A.; Laranjeiro Pinto, M.; Patrícia Cardoso, A.; Monteiro, C.; Teixeira Pinto, M.; Filipe Maia, A.; Castro, P.; Figueira, R.; Monteiro, A.; Marques, M.; et al. Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities. Sci. Rep. 2016, 6, 18765. [Google Scholar] [CrossRef]
- Jiang, H.; Hegde, S.; DeNardo, D.G. Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy. Cancer Immunol. Immunother. 2017, 66, 1037–1048. [Google Scholar] [CrossRef]
- Piper, M.; Mueller, A.C.; Karam, S.D. The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy. Mol. Carcinog. 2020, 59, 754–765. [Google Scholar] [CrossRef]
- Vallée, A.; Lecarpentier, Y.; Guillevin, R.; Vallée, J.N. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget 2017, 8, 90579–90604. [Google Scholar] [CrossRef]
- Genard, G.; Lucas, S.; Michiels, C. Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies. Front. Immunol. 2017, 8, 828. [Google Scholar] [CrossRef]
- Klug, F.; Prakash, H.; Huber, P.E.; Seibel, T.; Bender, N.; Halama, N.; Pfirschke, C.; Voss, R.H.; Timke, C.; Umansky, L.; et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 2013, 24, 589–602. [Google Scholar] [CrossRef]
- Collett, G.P.; Campbell, F.C. Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells. Carcinogenesis 2006, 27, 1285–1291. [Google Scholar] [CrossRef]
- Schwarz, K.; Dobiasch, S.; Nguyen, L.; Schilling, D.; Combs, S.E. Modification of radiosensitivity by Curcumin in human pancreatic cancer cell lines. Sci. Rep. 2020, 10, 3815. [Google Scholar] [CrossRef]
- Paul, S.; Sa, G. Curcumin as an Adjuvant to Cancer Immunotherapy. Front. Oncol. 2021, 11, 675923. [Google Scholar] [CrossRef]
- Fu, X.; He, Y.; Li, M.; Huang, Z.; Najafi, M. Targeting of the tumor microenvironment by curcumin. Biofactors 2021, 47, 914–932. [Google Scholar] [CrossRef]
- Bhattacharyya, S.; Md Sakib Hossain, D.; Mohanty, S.; Sankar Sen, G.; Chattopadhyay, S.; Banerjee, S.; Chakraborty, J.; Das, K.; Sarkar, D.; Das, T.; et al. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell. Mol. Immunol. 2010, 7, 306–315. [Google Scholar] [CrossRef]
- MaruYama, T.; Kobayashi, S.; Nakatsukasa, H.; Moritoki, Y.; Taguchi, D.; Sunagawa, Y.; Morimoto, T.; Asao, A.; Jin, W.; Owada, Y.; et al. The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells. Front. Immunol. 2021, 12, 687669. [Google Scholar] [CrossRef]
- Massoud, T.F.; Gambhir, S.S. Molecular imaging in living subjects: Seeing fundamental biological processes in a new light. Genes. Dev. 2003, 17, 545–580. [Google Scholar] [CrossRef]
- Alam, I.S.; Mayer, A.T.; Sagiv-Barfi, I.; Wang, K.; Vermesh, O.; Czerwinski, D.K.; Johnson, E.M.; James, M.L.; Levy, R.; Gambhir, S.S. Imaging activated T cells predicts response to cancer vaccines. J. Clin. Investig. 2018, 128, 2569–2580. [Google Scholar] [CrossRef] [PubMed]
- Liao, F.; Liu, L.; Luo, E.; Hu, J. Curcumin enhances anti-tumor immune response in tongue squamous cell carcinoma. Arch. Oral. Biol. 2018, 92, 32–37. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Li, L.; Zhang, B.; Xu, Z.P. MnO2-shelled Doxorubicin/Curcumin nanoformulation for enhanced colorectal cancer chemo-immunotherapy. J. Colloid. Interface Sci. 2022, 617, 315–325. [Google Scholar] [CrossRef] [PubMed]
- Hussain, Y.; Islam, L.; Khan, H.; Filosa, R.; Aschner, M.; Javed, S. Curcumin-cisplatin chemotherapy: A novel strategy in promoting chemotherapy efficacy and reducing side effects. Phytother. Res. 2021, 35, 6514–6529. [Google Scholar] [CrossRef] [PubMed]
- Karavasili, C.; Andreadis, D.A.; Katsamenis, O.L.; Panteris, E.; Anastasiadou, P.; Kakazanis, Z.; Zoumpourlis, V.; Markopoulou, C.K.; Koutsopoulos, S.; Vizirianakis, I.S.; et al. Synergistic Antitumor Potency of a Self-Assembling Peptide Hydrogel for the Local Co-delivery of Doxorubicin and Curcumin in the Treatment of Head and Neck Cancer. Mol. Pharm. 2019, 16, 2326–2341. [Google Scholar] [CrossRef] [PubMed]
- Howells, L.M.; Iwuji, C.O.O.; Irving, G.R.B.; Barber, S.; Walter, H.; Sidat, Z.; Griffin-Teall, N.; Singh, R.; Foreman, N.; Patel, S.R.; et al. Curcumin Combined with FOLFOX Chemotherapy Is Safe and Tolerable in Patients with Metastatic Colorectal Cancer in a Randomized Phase IIa Trial. J. Nutr. 2019, 149, 1133–1139. [Google Scholar] [CrossRef]
- Yang, J.; Zhu, D.; Liu, S.; Shao, M.; Liu, Y.; Li, A.; Lv, Y.; Huang, M.; Lou, D.; Fan, Q. Curcumin enhances radiosensitization of nasopharyngeal carcinoma by regulating circRNA network. Mol. Carcinog. 2020, 59, 202–214. [Google Scholar] [CrossRef]
- Azzi, J.; Waked, A.; Bou-Gharios, J.; Al Choboq, J.; Geara, F.; Bodgi, L.; Maalouf, M. Radiosensitizing Effect of Curcumin on Human Bladder Cancer Cell Lines: Impact on DNA Repair Mechanisms. Nutr. Cancer 2022, 74, 2207–2221. [Google Scholar] [CrossRef]
- Kim, J.-Y.; Jung, C.-W.; Lee, W.S.; Kim, H.-J.; Jeong, H.-J.; Park, M.-J.; Jang, W.I.; Kim, E.H. Interaction of curcumin with glioblastoma cells via high and low linear energy transfer radiation therapy inducing radiosensitization effects. J. Radiat. Res. 2022, 63, 342–353. [Google Scholar] [CrossRef]
- Farhood, B.; Mortezaee, K.; Goradel, N.H.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Najafi, M.; Sahebkar, A. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J. Cell. Physiol. 2019, 234, 5728–5740. [Google Scholar] [CrossRef]
- Bruzzese, L.; Fromonot, J.; By, Y.; Durand-Gorde, J.-M.; Condo, J.; Kipson, N.; Guieu, R.; Fenouillet, E.; Ruf, J. NF-κB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A2A receptors. Cell Signal. 2014, 26, 1060–1067. [Google Scholar] [CrossRef]
- Tang, K.H.; Li, S.; Khodadadi-Jamayran, A.; Jen, J.; Han, H.; Guidry, K.; Chen, T.; Hao, Y.; Fedele, C.; Zebala, J.A.; et al. Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC. Cancer Discov. 2022, 12, 47–61. [Google Scholar] [CrossRef]
- Alsaab, H.O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S.K.; Iyer, A.K. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol. 2017, 8, 561. [Google Scholar] [CrossRef]
- Croft, M.; So, T.; Duan, W.; Soroosh, P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol. Rev. 2009, 229, 173–191. [Google Scholar] [CrossRef]
- He, K.; Liu, P.; Xu, L.X. The cryo-thermal therapy eradicated melanoma in mice by eliciting CD4+ T-cell-mediated antitumor memory immune response. Cell Death Dis. 2017, 8, e2703. [Google Scholar] [CrossRef]
- Sckisel, G.D.; Mirsoian, A.; Minnar, C.M.; Crittenden, M.; Curti, B.; Chen, J.Q.; Blazar, B.R.; Borowsky, A.D.; Monjazeb, A.M.; Murphy, W.J. Differential phenotypes of memory CD4 and CD8 T cells in the spleen and peripheral tissues following immunostimulatory therapy. J. Immunother. Cancer 2017, 5, 33. [Google Scholar] [CrossRef]
- Liu, L.; Lim, M.A.; Jung, S.-N.; Oh, C.; Won, H.-R.; Jin, Y.L.; Piao, Y.; Kim, H.J.; Chang, J.W.; Koo, B.S. The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer. Phytomedicine 2021, 92, 153758. [Google Scholar] [CrossRef]
- Chang, Y.-F.; Chuang, H.-Y.; Hsu, C.-H.; Liu, R.-S.; Gambhir, S.S.; Hwang, J.-J. Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice. Cancer Prev. Res. 2012, 5, 444–452. [Google Scholar] [CrossRef]
- Papageorgis, P.; Stylianopoulos, T. Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review). Int. J. Oncol. 2015, 46, 933–943. [Google Scholar] [CrossRef]
- Bellomo, C.; Caja, L.; Moustakas, A. Transforming growth factor β as regulator of cancer stemness and metastasis. Br. J. Cancer 2016, 115, 761–769. [Google Scholar] [CrossRef]
- Horn, L.A.; Chariou, P.L.; Gameiro, S.R.; Qin, H.; Iida, M.; Fousek, K.; Meyer, T.J.; Cam, M.; Flies, D.; Langermann, S.; et al. Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication. J. Clin. Investig. 2022, 132, e155148. [Google Scholar] [CrossRef] [PubMed]
- Mojic, M.; Takeda, K.; Hayakawa, Y. The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion. Int. J. Mol. Sci. 2018, 19, 89. [Google Scholar] [CrossRef] [PubMed]
- Castro, F.; Cardoso, A.P.; Gonçalves, R.M.; Serre, K.; Oliveira, M.J. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front. Immunol. 2018, 9, 847. [Google Scholar] [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Shih, K.-C.; Chan, H.-W.; Wu, C.-Y.; Chuang, H.-Y. Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator. Pharmaceutics 2023, 15, 1519. https://doi.org/10.3390/pharmaceutics15051519
Shih K-C, Chan H-W, Wu C-Y, Chuang H-Y. Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator. Pharmaceutics. 2023; 15(5):1519. https://doi.org/10.3390/pharmaceutics15051519
Chicago/Turabian StyleShih, Kuang-Chung, Hui-Wen Chan, Chun-Yi Wu, and Hui-Yen Chuang. 2023. "Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator" Pharmaceutics 15, no. 5: 1519. https://doi.org/10.3390/pharmaceutics15051519