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Anticancer Effect of Ruscogenin in B(a)P-Induced Lung Cancer in Mice via Modulation of Proinflammatory Cytokines and Mitochondrial Enzymes

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Abstract

Lung cancer, one of the most often diagnosed malignancies, is the top cause of death in both men and women globally. In both developed and emerging countries, high incidences of cancer are becoming a huge health burden. Natural resources, including plants, have always been a possible source of lead compounds in the identification of optimal medications for cancer treatment, with natural resources accounting for around half of all anticancer drugs. Ruscogenin, a natural saponin, is a major component of Radix Ophiopogon japonicus with a well-established anticancer activity. In this study, the anticancer potential of ruscogenin against a B(a)P-challenged lung cancer model in mice was assessed. The mice were categorized into four groups: group I was as the control group, group II mice were challenged with B(a)P, group III rodents were treated with ruscogenin prior to challenge with B(a)P, and group IV rodents were treated with ruscogenin after B(a)P administration. Tumor incidence was calculated, and the following parameters were analyzed: body weight, lung weight, immunoglobulin (Ig) levels (IgG, IgA, and IgM), key marker enzymes, and proinflammatory cytokines in both treated and control mice. Lung tissues were analyzed via histopathological analysis. According to our results, all the markers that favor the growth of cancer were increased in the lung cancer group. After administration of ruscogenin, all the markers returned to their original levels, revealing the anticancer potential of ruscogenin.

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Abbreviations

Ig:

Immunoglobulin

B(a)P:

Benzo[a]pyrene

TCM:

Traditional Chinese medicine

GGT:

Gamma-glutamyl transferase

ADA:

Adenosine deaminase

LDH:

Lactate dehydrogenase

AAH:

Aryl hydrocarbon hydroxylase

5′-NT:

5′-Nucleotidase

CEA:

Carcinoembryonic antigen

ICDH:

Isocitrate dehydrogenase

SDH:

Succinate dehydrogenase

References

  1. Wang, X., Veeraraghavan, V. P., Mohan, S. K., & Lv, F. (2021). Anticancer and immunomodulatory effect of rhaponticin on benzo (a) pyrene-induced lung carcinogenesis and induction of apoptosis in A549 cells. Saudi Journal of Biological Sciences., 28(8), 4522–4531.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. World Health Organization (WHO). (2021). Global cancer observatory: Cancer today. Available from: http://gco.iarc.fr.

  3. Khan, A., Alhumaydhi, F. A., Alwashmi, A. S., Allemailem, K. S., Alsahli, M. A., Alrumaihi, F. A., Almatroudi, A., Mobark, M. A., Mousa, A., & Khan, M. A. (2020). Diallyl sulfide-mediated modulation of the fatty acid synthase (FASN) leads to cancer cell death in bap-induced lung carcinogenesis in Swiss mice. Journal of Inflammation Research., 13, 1075.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Barta, J. A., Powell, C. A., & Wisnivesky, J. P. (2019). Global epidemiology of lung cancer. Annals of Global Health., 85(1), 8. https://doi.org/10.5334/aogh.2419.

  5. Liu, J., Yang, Z., Kong, Y., He, Y., Xu, Y., & Cao, X. (2019). Antitumor activity of alantolactone in lung cancer cell lines NCI-H1299 and Anip973. Journal of Food Biochemistry., 43(9), e12972.

    Article  PubMed  Google Scholar 

  6. Ramalingam, V., & Rajaram, R. (2018). Enhanced antimicrobial, antioxidant and anticancer activity of Rhizophora apiculata: An experimental report. 3 Biotech., 8(4), 1–3.

    Article  Google Scholar 

  7. Wang, C. C., Yuan, J. R., Wang, C. F., Yang, N., Chen, J., Liu, D., Song, J., Feng, L., Tan, X. B., & Jia, X. B. (2017). Anti-inflammatory effects of Phyllanthus emblica L on benzopyrene-induced precancerous lung lesion by regulating the IL-1β/miR-101/Lin28B signaling pathway. Integrative Cancer Therapies., 16(4), 505–515.

    Article  PubMed  CAS  Google Scholar 

  8. Xiao, B., Lin, D., Zhang, X., Zhang, M., & Zhang, X. (2016). TTF1, in the form of nanoparticles, inhibits angiogenesis, cell migration and cell invasion in vitro and in vivo in human hepatoma through STAT3 regulation. Molecules, 21(11), 1507.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shendge, A. K., Sarkar, R., & Mandal, N. (2020). Potent anti-inflammatory Terminalia chebula fruit showed in vitro anticancer activity on lung and breast carcinoma cells through the regulation of Bax/Bcl-2 and caspase-cascade pathways. Journal of Food Biochemistry., 44(12), e13521.

    Article  PubMed  CAS  Google Scholar 

  10. Hua, H., Zhu, Y., & Song, Y. H. (2018). Ruscogenin suppressed the hepatocellular carcinoma metastasis via PI3K/Akt/mTOR signaling pathway. Biomedicine & Pharmacotherapy., 101, 115–122.

    Article  CAS  Google Scholar 

  11. Khojasteh, A., Sanchez-Muñoz, R., Moyano, E., Bonfill, M., Cusido, R. M., Eibl, R., & Palazon, J. (2019). Biotechnological production of ruscogenins in plant cell and organ cultures of Ruscus aculeatus. Plant Physiology and Biochemistry., 141, 133–141.

    Article  PubMed  CAS  Google Scholar 

  12. Song, Z., Xiang, X., Li, J., Deng, J., Fang, Z., Zhang, L., & Xiong, J. (2020). Ruscogenin induces ferroptosis in pancreatic cancer cells. Oncology Reports., 43(2), 516–524.

    PubMed  CAS  Google Scholar 

  13. Ma, A. Z. (2014). Mechanism of ruscogenin on suppressing pulmonary A549 and H460 cells. Nanjing University of Chinese Medicine.

    Google Scholar 

  14. Tennant, B., Baldwin, B. H., Braun, R. K., Norcross, N. L., & Sandholm, M. (1979). Use of the glutaraldehyde coagulation test for deduction of hypogammaglobulinemia in neonatal calves. Journal of the American Veterinary Medical Association, 174, 848–853.

    PubMed  CAS  Google Scholar 

  15. Satpathy, P. K., Dutta, N. K., Mishra, P. R., & Kai, B. (1996). Glutaraldehyde coagulation test: Standard curve and its applications to detect gammaglobulin level in kids. The Indian Veterinary Journal, 73(3), 257–260.

    CAS  Google Scholar 

  16. Bergmeyer, H.U. (1984). Principles of enzymatic analysis. In: Methods of enzymatic analysis. Verlag Chemie

  17. Buening, M. K., Chang, R. L., Huang, M. T., Fortner, J. G., Wood, A. W., & Conney, A. H. (1981). Activation and inhibition of benzo (a) pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids. Cancer Research, 41(1), 67–72.

    PubMed  CAS  Google Scholar 

  18. Orlowski, M., & Meister, A. (1965). Isolation of γ-glutamyl transpeptidase from hog kidney. Journal of Biological Chemistry, 240, 338–347.

    Article  PubMed  CAS  Google Scholar 

  19. Luly, P., Barnabei, O., & Tria, E. (1972). Hormonal control in vitro of plasma membrane-bound (Na+− K+)-ATPase of rat liver. Biochimica Et Biophysica Acta, 282, 447–452.

    Article  PubMed  CAS  Google Scholar 

  20. King, C. (1965). The transferases-alanine and aspartate transaminases. In D. Van (Ed.), Practical Clinical Enzymology (pp. 121–138). Nostrand Company Ltd.

    Google Scholar 

  21. Wharton, D. C., & Tzagoloff, A. (1967). Methods in Enzymology (pp. 245–250). Academic Press.

    Google Scholar 

  22. Omura, T., & Sato, R. (1964). The carbon monoxide-binding pigment of liver microsomes: I. Evidence for its hemoprotein nature. Journal of Biological Chemistry, 239(7), 2370–2378.

    Article  PubMed  CAS  Google Scholar 

  23. Benson, A. M., Hunkeler, M. J., & Talalay, P. (1980). Increase of NAD (P) H: Quinone reductase by dietary antioxidants: Possible role in protection against carcinogenesis and toxicity. Proceedings of the National Academy of Sciences, 77(9), 5216–5220.

    Article  CAS  Google Scholar 

  24. Luquita, M. G., Sánchez Pozzi, E. J., Catania, V. A., & Mottino, A. D. (1994). Analysis of p-nitrophenol glucuronidation in hepatic microsomes from lactating rats. Biochemical Pharmacology, 47(7), 1179–1185.

    Article  PubMed  CAS  Google Scholar 

  25. Habig, W. H., Pabst, M. J., & Jakoby, W. B. (1974). Glutathione S-transferases: The first enzymatic step in mercapturic acid formation. Journal of Biological Chemistry, 249(22), 7130–7139.

    Article  PubMed  CAS  Google Scholar 

  26. Naveenkumar, C., Asokkumar, S., Raghunandhakumar, S., Jagan, S., Anandakumar, P., Augustine, T. A., Kamaraj, S., & Devaki, T. (2012). Potent antitumor and antineoplastic efficacy of baicalein on benzo (a) pyrene-induced experimental pulmonary tumorigenesis. Fundamental and Clinical Pharmacology, 2(2), 259–270.

    Article  Google Scholar 

  27. Johnson, D., & Lardy, H. (1967). Isolation of liver or kidney mitochondria. Methods in Enzymology, 10, 94–96.

    Article  CAS  Google Scholar 

  28. Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265–275.

    Article  PubMed  CAS  Google Scholar 

  29. Reed, L. J., & Mukherjee, B. B. (1969). Methods in enzymology (pp. 55–61). Academic Press.

    Google Scholar 

  30. Slater, E. C., & Borner, W. D. (1952). The effect of fluoride on succinic oxidase system. The Biochemical Journal, 52, 185–196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Mehler, A. H., & Kornberg, A. (1948). The enzymatic mechanism of oxidation-reductions between malate or isocitrate and pyruvate. Journal of Biological Chemistry, 174, 961–977.

    Article  PubMed  CAS  Google Scholar 

  32. Birchmachin, M. A., Briggs, H. L., Saborido, A. A., Bindoff, L. A., & Turnbull, D. M. (1994). An evaluation of the measurement of the activities of complexes I-IV in the respiratory chain of human skeletal muscle mitochondria. Biochemical Medicine and Metabolic Biology, 51(1), 35–42.

    Article  PubMed  CAS  Google Scholar 

  33. Krähenbühl, S., Talos, C., Wiesmann, U., & Hoppel, C. L. (1994). Development and evaluation of a spectrophotometric assay for complex III in isolated mitochondria, tissues and fibroblasts from rats and humans. Clinica Chimica Acta, 230(2), 177–187.

    Article  Google Scholar 

  34. Capaldi, R. A., Maruschi, M. F., & Taanman, J. W. (1995). Methods of Biochemical Analysis, 2, 427–434.

    Google Scholar 

  35. Cicko, S., Lucattelli, M., Muller, T., Lommatzsch, M., De Cunto, G., et al. (2010). Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. The Journal of Immunology, 185, 688–697.

    Article  PubMed  CAS  Google Scholar 

  36. Hu, X., Geetha, R. V., Surapaneni, K. M., Veeraraghavan, V. P., Chinnathambi, A., Alahmadi, T. A., Manikandan, V., & Manokaran, K. (2021). Lung cancer induced by benzo(A)pyrene: Chemoprotective effect of sinapic acid in Swiss albino mice. Saudi Journal of Biological Sciences, 28(12), 7125–7133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Arumugam, P., Arunkumar, K., Sivakumar, L., Murugan, M., & Murugan, K. (2019). Anticancer effect of fucoidan on cell proliferation, cell cycle progression, genetic damage and apoptotic cell death in HepG2 cancer cells. Toxicology Reports., 6, 556–563.

    Article  Google Scholar 

  38. Gong, C., Qi, L., Huo, Y., Zhang, S., Ning, X., Bai, L., & Wang, Z. (2019). Anticancer effect of Limonin against benzo (a) pyrene-induced lung carcinogenesis in Swiss albino mice and the inhibition of A549 cell proliferation through apoptotic pathway. Journal of Biochemical and Molecular Toxicology., 33(12), e22374.

    Article  PubMed  CAS  Google Scholar 

  39. Hassan, S. K., Mousa, A. M., El-Sammad, N. M., Abdel-Halim, A. H., Khalil, W. K., Elsayed, E. A., Anwar, N., Linscheid, M. W., Moustafa, E. S., Hashim, A. N., & Nawwar, M. (2019). Antitumor activity of Cuphea ignea extract against benzo (a) pyrene-induced lung tumorigenesis in Swiss Albino mice. Toxicology Reports., 6, 1071–1085.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Velli, S. K., Sundaram, J., Murugan, M., Balaraman, G., & Thiruvengadam, D. (2019). Protective effect of vanillic acid against benzo (a) pyrene induced lung cancer in Swiss albino mice. Journal of Biochemical and Molecular Toxicology., 33(10), e22382.

    Article  PubMed  CAS  Google Scholar 

  41. Yoon, S. H. (2014). Immunotherapy for non-small cell lung cancer. Tuberculosis and Respiratory Diseases., 77(3), 111–115.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Singh, N., Baby, D., Rajguru, J. P., Patil, P. B., Thakkannavar, S. S., & Pujari, V. B. (2019). Inflammation and cancer. Annals of African Medicine., 18(3), 121.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gào, X., Xuan, Y., Benner, A., Anusruti, A., Brenner, H., & Schöttker, B. (2019). Nitric oxide metabolites and lung cancer incidence: A matched case-control study nested in the ESTHER cohort. Oxidative Medicine and Cellular Longevity., 2019, 6470950. https://doi.org/10.1155/2019/6470950.

  44. Zhao, P., & Zhang, Z. (2018). TNF-α promotes colon cancer cell migration and invasion by upregulating TROP-2. Oncology letters., 15(3), 3820–3827.

    PubMed  PubMed Central  Google Scholar 

  45. Kasala, E. R., Bodduluru, L. N., Barua, C. C., Sriram, C. S., & Gogoi, R. (2015). Benzo (a) pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention. Pharmacological Reports., 67(5), 996–1009.

    Article  PubMed  CAS  Google Scholar 

  46. Rao, P. S., Midde, N., Miller, D., Chauhan, S., Kumar, A., & Kumar, S. (2015). Diallyl sulfide: Potential use in novel therapeutic interventions in alcohol, drugs, and disease mediated cellular toxicity by targeting cytochrome P450 2E1. Current Drug Metabolism., 16(6), 486–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Miao, P., Sheng, S., Sun, X., Liu, J., & Huang, G. (2013). Lactate dehydrogenase A in cancer: A promising target for diagnosis and therapy. IUBMB Life, 65(11), 904–910.

    Article  PubMed  CAS  Google Scholar 

  48. Xie, H., Hanai, J. I., Ren, J. G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K. J., Grant, A., & Wang, X. (2014). Targeting lactate dehydrogenase-a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metabolism., 19(5), 795–809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Beauchemin, N., & Arabzadeh, A. (2013). Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer and Metastasis Reviews., 32(3), 643–671.

    Article  PubMed  CAS  Google Scholar 

  50. Thirunavukkarasu, C., Prince Vijeya Singh, J., Selvendiran, K., & Sakthisekaran, D. (2001). Chemopreventive efficacy of selenium against N-nitrosodiethylamine-induced hepatoma in albino rats. Cell Biochemistry and Function: Cellular Biochemistry and its Modulation by Active Agents or Disease., 19(4), 265–71.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Respiratory, Jiyang People’s Hospital of Jinan, Jinan City, 251400, Shandong Province, China

    Jun Zhao

  2. Department of Comprehensive Medicine, Jiyang People’s Hospital of Jinan, Jinan City, 251400, Shandong Province, China

    Bangzhi He

  3. Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdul Aziz University, Al-Kharj, Kingdom of Saudi Arabia

    Vidya Devanathadesikan Seshadri

  4. Department of Respiratory and Critical Care Medicine, The Second Hospital of Shandong University, No. 247, Beiyuan Road, Shandong Province, 250033, Jinan City, China

    Shaohua Xu

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  1. Jun Zhao
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  2. Bangzhi He
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Jun Zhao, Bangzhi He, Vidya Devanathadesikan Seshadri, and Shaohua Xu contributed equally in working and drafting the manuscript.

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Correspondence to Shaohua Xu.

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Zhao, J., He, B., Seshadri, V.D. et al. Anticancer Effect of Ruscogenin in B(a)P-Induced Lung Cancer in Mice via Modulation of Proinflammatory Cytokines and Mitochondrial Enzymes. Appl Biochem Biotechnol 194, 5862–5877 (2022). https://doi.org/10.1007/s12010-022-04042-z

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