Evaluation of lactoferrin combined hyaluronic acid formulations with the help of hyperthermia on breast cancer cell lines
Abstract
Lactoferrin is a potential anticancer protein naturally found in mammalian secretions. It shows anti- proliferative effects on various cancer types in vitro and in vivo. Its activity is highly associated with the immune system and its complements. On the other hand, hyperthermia is a type of cancer therapy in which tissues are exposed to heat at a temperature in the range of 40ºC-44ºC which induces apoptosis and necrosis. Hyperthermia normally aims to improve the results of conventional treatment strategies such as chemo or radiotherapy. The study aimed to enhance the lactoferrin effect with hyperthermia. Hyaluronic acid was additionally used in the formulation to augment the anticancer effect of lactoferrin. MTT Assays were performed for cell viability at 24 and 72 hours after the lactoferrin, hyaluronic acid, and hyperthermia treatment on MCF-7, MDA-MB 231, and HDF cell lines in vitro. No anticancer efficacy of lactoferrin was observed. However, it was demonstrated that Hyaluronic acid enhanced the anti-proliferative efficacy of hyperthermia treatment, and significant reductions in the cell viability were observed after 24 hours on MCF-7 cells in a p53-dependent manner whereas no reduction in the cell viability of MDAMB 231 and HDF cells. Mutation on the p53 gene of MDA-MB 231 cells possibly prevented the heat-induced apoptosis. Hyaluronic acid-induced cell death was observed 72 hours after the treatment independently from the heat exposure group. No cytotoxicity was observed on the HDF cell line. The activity could not be obtained from the pure hyaluronic acid solution. Subsequent determination of the chemical responsible for the anticancer efficacy should be performed. This research could lead to the discovery of a new selective chemotherapeutic agent that can be used in breast cancer.
References
- [1] Zhang Y, Lima CF, Rodrigues LR. Anticancer effects of lactoferrin: Underlying mechanisms and future trends in cancer therapy. Nutr Rev. 2014;72(12):763-773. https://doi.org/10.1111/nure.12155.
- [2] Pereira CS, Guedes JP, Gonçalves M, Loureiro L, Castro L, Gerós H, Rodrigues LR, Côrte-Real M. Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase. Oncotarget. 2016;7(38):62144-62158. https://doi.org/10.18632/oncotarget.11394.
- [3] Giansanti F, Panella G, Leboffe L, Antonini G. Lactoferrin from Milk: Nutraceutical and Pharmacological Properties. Pharmaceuticals (Basel). 2016;9(4):61. https://doi.org/10.3390/ph9040061.
- [4] Tsuda H, Kozu T, Iinuma G, Ohashi Y, Saito Y, Saito D, Akasu T, Alexander DB, Futakuchi M, Fukamachi K, Xu J, Kakizoe T, Iigo M. Cancer prevention by bovine lactoferrin: from animal studies to human trial. Biometals. 2010;23(3):399-409. https://doi.org/10.1007/s10534-010-9331-3.
- [5] Kruzel ML, Zimecki M, Actor JK. Lactoferrin in a Context of Inflammation-Induced Pathology. Front Immunol. 2017;8:1438. https://doi.org/10.3389/fimmu.2017.01438.
- [6] Wolf JS, Li G, Varadhachary A, Petrak K, Schneyer M, Li D, Ongkasuwan J, Zhang X, Taylor RJ, Strome SE, O'Malley BW Jr. Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo. Clin Cancer Res. 2007;13(5):1601-1610. https://doi.org/10.1158/1078-0432.ccr-06-2008.
- [7] Huang G, Huang H. Application of hyaluronic acid as carriers in drug delivery. Drug Deliv. 2018;25(1):766-772. https://doi.org/10.1080/10717544.2018.1450910.
- [8] Mattheolabakis G, Milane L, Singh A, Amiji MM. Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine. J Drug Target. 2015;23(7-8):605-618. https://doi.org/10.3109/1061186x.2015.1052072.
- [9] Huang G, Huang H. Hyaluronic acid-based biopharmaceutical delivery and tumor-targeted drug delivery system. J Control Release. 2018;278:122-126. https://doi.org/10.1016/j.jconrel.2018.04.015.
- [10] Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002;43(1):33-56. https://doi.org/10.1016/s1040-8428(01)00179-2.
- [11] Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM. Hyperthermia in combined treatment of cancer. Lancet Oncol. 2002;3(8):487-97. https://doi.org/10.1016/s1470-2045(02)00818-5.
- [12] Chu KF, Dupuy DE. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer. 2014;14(3):199-208. https://doi.org/10.1038/nrc3672.
- [13] Skitzki JJ, Repasky EA, Evans SS. Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs. 2009;10(6):550-558.
- [14] Kalamida D, Karagounis IV, Mitrakas A, Kalamida S, Giatromanolaki A, Koukourakis MI. Fever-range hyperthermia vs. hypothermia effect on cancer cell viability, proliferation and HSP90 expression. PLoS One. 2015;10(1):e0116021. https://doi.org/10.1371/journal.pone.0116021.
- [15] Luo Z, Zheng K, Fan Q, Jiang X, Xiong D. Hyperthermia exposure induces apoptosis and inhibits proliferation in HCT116 cells by upregulating miR-34a and causing transcriptional activation of p53. Exp Ther Med. 2017;14(6):5379-5386. https://doi.org/10.3892/etm.2017.5257.
Details
| Primary Language | English |
|---|---|
| Subjects | Pharmaceutical Delivery Technologies |
| Journal Section | Articles |
| Authors | |
| Publication Date | June 28, 2025 |
| Submission Date | July 29, 2024 |
| Acceptance Date | August 16, 2024 |
| Published in Issue | Year 2024 Volume: 28 Issue: 5 |