Levels of growth factors in the lungs affected by cancer with preventive effect of 1,3-diethylbenzimidazolium triiodide in the experiment

Purpose of the study. Analyzing the dynamics of VEGF-А, TGF-β and their receptors in the lung tissues in rats with antitumor effect of 1,3-diethylbenzimidazolium triiodide (Stellanin).

Material and methods. The study included white outbred rats weighing 180–220 g. The main group included males (n=27) and females (n=27) with sarcoma 45 (s45) inoculated into the subclavian vein but not developed in the lungs (2×106 cells in 0.5 ml of saline) due to the subsequent intragastric administration of Stellanin (0.4 mg/kg once a day) according to an intermittent scheme: administration for 5 days and a break for 2 days. The control group included males (n=14) and females (n=14) without treatment with growing s45 in the lungs. Intact groups included 5 males and 5 females. After 4, 5 and 8 weeks of the experiment animals were decapitated, and levels of VEGF-A, sVEGF-R1, sVEGF-R2, TGF-β and sTGFβR2 were measured in 10% lung homogenates by ELISA (CUSABIO BIOTECH Co., Ltd., China).

Results. Lung tissues of intact females showed 1.4 times (p<0.05) lower VEGF-А and 3.3 times higher sVEGF-R1, compared to males. The development of tumors in all control rats was accompanied by the VEGF-А increase (by 1.6–3.0 times) and the TGF-β reduction (by 3 times). The dynamics of both VEGF receptors differed in males and females. The levels of sVEGF-R1 in males increased by 1.5 times (p<0.05), while in females it decreased by 1.8 times (p<0.05), and as a result, the levels became similar in all animals. The levels of sVEGF-R2 in males decreased by 2 times, and in females it increased by 1.4 times (p<0.05), so the sVEGF-R2 content in females became 2.4 times higher than in males. In two-thirds of rats, Stellanin prevented s45 development in the lungs due to inhibition of VEGF-A growth by more than 2.0 times and an increase in concentrations of sVEGF-R1 by 10.0 times and TGF-β by 6.0 times, together with normalization of sVEGF-R2 and sTGFβR2.

Conclusions. Stellanin prevents the development of malignant process in the lungs by inhibiting neoangiogenesis (deficiency of VEGF-A and excess of sVEGF-R1) and suppressing the proliferation of malignant cells (TGF-β growth).

1. Shankar A, Dubey A, Saini D, Singh M, Prasad CP, Roy S, et al. Environmental and occupational determinants of lung cancer. Transl Lung Cancer Res. 2019 May;8(Suppl 1):S31–49. https://doi.org/10.21037/tlcr.2019.03.05

2. Kessler JH. The effect of supraphysiologic levels of iodine on patients with cyclic mastalgia. Breast J. 2004 Aug;10(4):328–336. https://doi.org/10.1111/j.1075-122X.2004.21341.x

3. Mendieta I, Nuñez-Anita RE, Nava-Villalba M, Zambrano-Estrada X, Delgado-González E, Anguiano B, et al. Molecular iodine exerts antineoplastic effects by diminishing proliferation and invasive potential and activating the immune response in mammary cancer xenografts. BMC Cancer. 2019 Mar 22;19(1):261. https://doi.org/10.1186/s12885-019-5437-3

4. Winje IM, Sheng X, Hansson K-A, Solbrå A, Tennøe S, Saatciog- lu F, et al. Cachexia does not induce loss of myonuclei or muscle fibres during xenografted prostate cancer in mice. Acta Physiol (Oxf). 2019;225(3):e13204. https://doi.org/10.1111/apha.13204

5. Zambrano-Estrada X, Landaverde-Quiroz B, Dueñas-Bocanegra AA, De Paz-Campos MA, Hernández-Alberto G, Solorio-Perusquia B, et al. Molecular iodine/doxorubicin neoadjuvant treatment impair invasive capacity and attenuate side effect in canine mammary cancer. BMC Vet Res. 2018 Mar 12;14(1):87. https://doi.org/10.1186/s12917-018-1411-6

6. Bontempo A, Ugalde-Villanueva B, Delgado-González E, Rodríguez ÁL, Aceves C. Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin. Oncol Rep. 2017 Nov;38(5):2867–2876. https://doi.org/10.3892/or.2017.5934

7. Moreno-Vega A, Vega-Riveroll L, Ayala T, Peralta G, Torres-Martel JM, Rojas J, et al. Adjuvant Effect of Molecular Iodine in Conventional Chemotherapy for Breast Cancer. Randomized Pilot Study. Nutrients. 2019 Jul 17;11(7):1623. https://doi.org/10.3390/nu11071623

8. Sidorenko YuS, Frantsyants EM, Tkalya LD. A Method for reproducing the malignant process in an experiment. Patent No. 2388064. Effective date: 11.08.2010. Published: 27.04.2010, Byull. No. 12. (In Russian).

9. Shikhlyarova AI, Frantsiyants EM, Nepomnyashchaya EM, Komarova EF, Pogorelova YuA. Features of structural changes in the lungs of male and female rats with intravenous inoculation of sarcoma-45. Journal of Oncology Issues. 2010;56(5):632–637. (In Russian).

10. Kit OI, Frantsiyants EM, Dimitriadi SN, Shevchenko AN, Kaplieva IV, Trepitaki LK. Neoangiogenesis and fibrinolytic system biomarkers expression in the dynamics of experimental kidney ischemia in rats. Journal of Experimental and Clinical Urology. 2015;(1):20–23. (In Russian).

11. Frantsiyants EM, Kaplieva IV, Trepitaki LK, Stradomskiy BV. Method of lung metastasis prevention in experiment. Journal of Experimental and Clinical Pharmacology. 2018;81(10):20–24. (In Russian). https://doi.org/10.30906/0869-2092-2018-81-10-24-28

12. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE. 2001 Dec 11;2001(112):re21. https://doi.org/10.1126/stke.2001.112.re21

13. Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669–676. https://doi.org/10.1038/nm0603-669

14. Barratt SL, Flower VA, Pauling JD, Millar AB. VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease. Int J Mol Sci. 2018 Apr 24;19(5):1269. https://doi.org/10.3390/ijms19051269 15. Logan SM, Storey KB. Angiogenic signaling in the lungs of a metabolically suppressed hibernating mammal (Ictidomys tride-cemlineatus). PeerJ. 2019;7:e8116. https://doi.org/10.7717/peerj.8116

15. Abib Abib AL de O, Correia C de J, Armstrong-Jr R, Ricardo-da-Silva FY, Ferreira SG, Vidal-Dos-Santos M, et al. The influence of female sex hormones on lung inflammation after brain death – an experimental study. Transpl Int. 2020 Mar;33(3):279– 287. https://doi.org/10.1111/tri.13550

16. Gupta DK, Singh N, Sahu DK. TGF-β Mediated Crosstalk Between Malignant Hepatocyte and Tumor Microenvironment in Hepatocellular Carcinoma. Cancer Growth Metastasis. 2014;7:1–8. https://doi.org/10.4137/CGM.S14205

17. Kit OI, Frantsiyants EM, Kolesnikov EN, Cheryarina ND, Kozlova LS, Pogorelova YuA, et al Growth factors in tissues of esophageal cancer of different histogenesis. Journal of Modern problems of science and education. 2016;(2):12. (In Russian).

18. Trapeznikova MF, Glybin PV, Tumanyan VG, Gershtein ES, Dutov VV, Kushlinskii NE. Vascular endothelial growth factor and its second type receptor in serum in patients with kidney cancer. Journal of Clinical Gerontology. 2011;(9-10):14–19. (In Russian).

19. Thielemann A, Baszczuk A, Kopczyński Z, Kopczyński P, Grodecka-Gazdecka S. Clinical usefulness of assessing VEGF and soluble receptors sVEGFR-1 and sVEGFR-2 in women with breast cancer. Ann Agric Environ Med. 2013;20(2):293–297.

20. Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb Perspect Biol. 2016 May 2;8(5):a021873. https://doi.org/10.1101/cshperspect.a021873