Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Anti-Proliferative Activities of Vasicinone on Lung Carcinoma Cells Mediated via Activation of Both Mitochondria-Dependent and Independent Pathways

  • Dey, Tapan (Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology) ;
  • Dutta, Prachurjya (Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology) ;
  • Manna, Prasenjit (Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology) ;
  • Kalita, Jatin (Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology) ;
  • Boruah, Hari Prasanna Deka (Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology) ;
  • Buragohain, Alak Kumar (Centre for Biotechnology and Bioinformatics, Dibrugarh University) ;
  • Unni, Balagopalan (Biological Sciences, Assam Downtown University)
  • Received : 2017.04.27
  • Accepted : 2017.08.14
  • Published : 2018.07.01
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Abstract

Vasicinone, a quinazoline alkaloid from Adhatoda vasica Nees. is well known for its bronchodilator activity. However its anti-proliferative activities is yet to be elucidated. Here-in we investigated the anti-proliferative effect of vasicinone and its underlying mechanism against A549 lung carcinoma cells. The A549 cells upon treatment with various doses of vasicinone (10, 30, 50, $70{\mu}M$) for 72 h showed significant decrease in cell viability. Vasicinone treatment also showed DNA fragmentation, LDH leakage, and disruption of mitochondrial potential, and lower wound healing ability in A549 cells. The Annexin V/PI staining showed disrupted plasma membrane integrity and permeability of PI in treated cells. Moreover vasicinone treatment also lead to down regulation of Bcl-2, Fas death receptor and up regulation of PARP, BAD and cytochrome c, suggesting the anti-proliferative nature of vasicinone which mediated apoptosis through both Fas death receptors as well as Bcl-2 regulated signaling. Furthermore, our preliminary studies with vasicinone treatment also showed to lower the ROS levels in A549 cells and have potential free radical scavenging (DPPH, Hydroxyl) activity and ferric reducing power in cell free systems. Thus combining all, vasicinone may be used to develop a new therapeutic agent against oxidative stress induced lung cancer.

Keywords

References

  1. Amin, A. H. and Mehta, D. R. (1959) A bronchodilator alkaloid (vasicinone) from Adhatoda vasica Nees. Nature 184, 1317.
  2. Claeson, U. P., Malmfors, T., Wikman, G. and Bruhn, J. G. (2000) Adhatoda vasica: a critical review of ethnopharmacological and toxicological data. J. Ethnopharmacol. 72, 1-20. https://doi.org/10.1016/S0378-8741(00)00225-7
  3. Deb, L., Laishram, S., Khumukcham, N., Ningthoukhongjam, D., Nameirakpam, S. S., Dey, A., Moirangthem, D. S., Talukdar, N. C. and Ningthoukhongjam, T. R. (2015) Past, present and perspectives of Manipur traditional medicine: a major health care system available for rural population in the North-East India. J. Ethnopharmacol. 169, 387-400. https://doi.org/10.1016/j.jep.2014.12.074
  4. Dutta, P., Dey, T., Manna, P. and Kalita, J. (2016) Antioxidant potential of Vespa affinis L., a traditional edible insect species of North East India. PLoS ONE 11, e0156107. https://doi.org/10.1371/journal.pone.0156107
  5. Fawole, O. A., Amoo, S. O., Ndhlala, A. R., Light, M. E., Finnie, J. F. and Van Staden, J. (2010) Anti-inflammatory, anticholinesterase, antioxidant and phytochemical properties of medicinal plants used for pain-related ailments in South Africa. J. Ethnopharmacol. 127, 235-241. https://doi.org/10.1016/j.jep.2009.11.015
  6. Galluzzi, L., Zamzami, N., de La Motte Rouge, T., Lemaire, C., Brenner, C. and Kroemer, G. (2007) Methods for the assessment of mitochondrial membrane permeabilization in apoptosis. Apoptosis 12, 803-813. https://doi.org/10.1007/s10495-007-0720-1
  7. Gautam, C. S. and Sharma, P. L. (1982) Potentiation of oxytocin evoked responses by (+) sotalol deoxysotalol and Vasicine HCl on isolated rat and rabbit uterus. Indian J. Med. Res. 76 Suppl, 107-114.
  8. Gibbs B. F. (2009) Differential modulation of IgE- dependent activation of human basophils by ambraxol and related secretolytic analogues. Int. J. Immunopathol. Pharmacol. 22, 919-927. https://doi.org/10.1177/039463200902200407
  9. Grange, J. M. and Snell, N. J. (1996) Activity of bromhexine and ambroxol, semi-synthetic derivatives of vasicine from the Indian shrub Adhatoda vasica, against Mycobacterium tuberculosis in vitro. J. Ethnopharmacol. 50, 49-53. https://doi.org/10.1016/0378-8741(95)01331-8
  10. Gruber, H. E., Hoelscher, G. L., Bethea, S. and Hanley, E. N., Jr. (2015) Mitochondrial membrane potential and nuclear and gene expression changes during human disc cell apoptosis: in vitro and in vivo annulus findings. Spine 40, 876-882. https://doi.org/10.1097/BRS.0000000000000936
  11. Kitazumi, I., Maseki, Y., Nomura, Y., Shimanuki, A., Sugita, Y. and Tsukahara, M. (2010) Okadaic acid induces DNA fragmentation via caspase-3-dependent and caspase-3-independent pathways in Chinese hamster ovary (CHO)-K1 cells. FEBS J. 277, 404-412. https://doi.org/10.1111/j.1742-4658.2009.07493.x
  12. Kumar, B., Koul, S., Khandrika, L., Meacham, R. B. and Koul, H. K. (2008) Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 68, 1777-1785. https://doi.org/10.1158/0008-5472.CAN-07-5259
  13. Lee, I., Pecinova, A., Pecina, P., Neel, B. G., Araki, T., Kucherlapati, R., Roberts, A. E. and Huttemann, M. (2010) A suggested role for mitochondria in Noonan syndrome. Biochim. Biophys. Acta 1802, 275-283. https://doi.org/10.1016/j.bbadis.2009.10.005
  14. Liou, G. Y. and Storz, P. (2010) Reactive oxygen species in cancer. Free Radic. Res. 44, 479-496. https://doi.org/10.3109/10715761003667554
  15. Liu, W., Wang, Y., He, D. D., Li, S. P., Zhu, Y. D., Jiang, B., Cheng, X. M., Wang, Z. and Wang, C. H. (2015) Antitussive, expectorant, and bronchodilating effects of quinazoline alkaloids (${\pm}$)-vasicine, deoxyvasicine, and (${\pm}$)-vasicinone from aerial parts of Peganum harmala L. Phytomedicine 22, 1088-1095. https://doi.org/10.1016/j.phymed.2015.08.005
  16. Ly, J. D., Grubb, D. R. and Lawen, A. (2003) The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 8, 115-128. https://doi.org/10.1023/A:1022945107762
  17. Malik, P. S. and Raina, V. (2015) Lung cancer: prevalent trends & emerging concepts. Indian J. Med. Res. 141, 5-7. https://doi.org/10.4103/0971-5916.154479
  18. Manna, P., Das, J., Ghosh, J. and Sil, P. C. (2010) Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, $I{\kappa}Ba/NF-{\kappa}B$, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid. Free Radic. Biol. Med. 48, 1465-1484. https://doi.org/10.1016/j.freeradbiomed.2010.02.025
  19. Manna, P., Sinha, M. and Sil, P. C. (2008) Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid. Arch. Toxicol. 82, 137-149. https://doi.org/10.1007/s00204-007-0272-8
  20. Marsden, V. S., Ekert, P. G., Van Delft, M., Vaux, D. L., Adams, J. M. and Strasser, A. (2004) Bcl-2-regulated apoptosis and cytochrome c release can occur independently of both caspase-2 and caspase-9. J. Cell Biol. 165, 775-780. https://doi.org/10.1083/jcb.200312030
  21. Ningthoujam, S. S., Das Talukdar, A., Potsangbam, K. S. and Choudhury, M. D. (2013) Traditional uses of herbal vapour therapy in Manipur, North East India: an ethnobotanical survey. J. Ethnopharmacol. 147, 136-147. https://doi.org/10.1016/j.jep.2012.12.056
  22. Oberley, L. W. and Buettner, G. R. (1979) Role of superoxide dismutase in cancer: a review. Cancer Res. 39, 1141-1149.
  23. Oltra, A. M., Carbonell, F., Tormos, C., Iradi, A. and Saez, G. T. (2001) Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia. Free Radic. Biol. Med. 30, 1286-1292. https://doi.org/10.1016/S0891-5849(01)00521-4
  24. Pandita, K., Bhatia, M. S., Thappa, R. K., Agarwal, S. G., Dhar, K. L. and Atal, C. K. (1983) Seasonal variation of alkaloids of Adhatoda vasica and detection of glycosides and N-Oxides of vasicine and vasicinone. Planta Med. 48, 81-82. https://doi.org/10.1055/s-2007-969891
  25. Pinkoski, M. J., Brunner, T., Green, D. R. and Lin, T. (2000) Fas and Fas ligand in gut and liver. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G354-G366. https://doi.org/10.1152/ajpgi.2000.278.3.G354
  26. Qazi, A. K., Hussain, A., Aga, M. A., Ali, S., Taneja, S. C., Sharma, P. R., Saxena, A. K., Mondhe, D. M. and Hamid, A. (2014) Cell specific apoptosis by RLX is mediated by $NF{\kappa}B$ in human colon carcinoma HCT-116 cells. BMC Cell Biol. 15, 36. https://doi.org/10.1186/1471-2121-15-36
  27. Qazi, A. K., Hussain, A., Khan, S., Aga, M. A., Behl, A., Ali, S., Singh, S. K., Taneja, S. C., Shah, B. A., Saxena, A. K., Mondhe, D. M. and Hamid, A. (2015) Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer. Cancer Lett. 359, 47-56. https://doi.org/10.1016/j.canlet.2014.12.034
  28. Roy Choudhury, P., Dutta Choudhury, M., Ningthoujam, S. S., Das, D., Nath, D. and Das Talukdar, A. (2015) Ethnomedicinal plants used by traditional healers of North Tripura district, Tripura, North East India. J. Ethnopharmacol. 166, 135-148. https://doi.org/10.1016/j.jep.2015.03.026
  29. Shang, X., Guo, X., Li, B., Pan, H., Zhang, J., Zhang, Y. and Miao, X. (2016) Microwave-assisted extraction of three bioactive alkaloids from Peganum harmala L. and their acaricidal activity against Psoroptes cuniculi in vitro. J. Ethnopharmacol. 192, 350-361. https://doi.org/10.1016/j.jep.2016.07.057
  30. Shankar, R., Lavekar, G. S., Deb, S. and Sharma, B. K. (2012) Traditional healing practice and folk medicines used by Mishing community of North East India. J. Ayurveda Integr. Med. 3, 124-129. https://doi.org/10.4103/0975-9476.100171
  31. Shevyakov, S. V., Davydova, O. I., Kiselyov, A. S., Kravchenko, D. V., Ivachtchenko, A. V. and Krasavin, M. (2006a) Natural products as templates for bioactive compound libraries: part 2. Novel modifications of vasicine (peganine) core via efficient and regioselective generation of 3-lithiodeoxyvasicine and its stereoselective addition to aliphatic ketones section sign. Nat. Prod. Res. 20, 871-881. https://doi.org/10.1080/14786410500480993
  32. Shevyakov, S. V., Davydova, O. I., Pershin, D. G., Krasavin, M., Kravchenko, D. V., Kiselyov, A., Tkachenko, S. E. and Ivachtchenko, A. V. (2006b) Natural products as templates for bioactive compound libraries: synthesis of biaryl derivatives of (+/-)-vasicine. Nat. Prod. Res. 20, 735-741. https://doi.org/10.1080/14786410500247418
  33. Singh, B. and Sharma, R. A. (2013) Anti-inflammatory and antimicrobial properties of pyrroloquinazoline alkaloids from Adhatoda vasica Nees. Phytomedicine 20, 441-445. https://doi.org/10.1016/j.phymed.2012.12.015
  34. Skrzydlewska, E., Sulkowski, S., Koda, M., Zalewski, B., Kanczuga-Koda, L. and Sulkowska, M. (2005) Lipid peroxidation and antioxidant status in colorectal cancer. World J. Gastroenterol. 11, 403-406. https://doi.org/10.3748/wjg.v11.i3.403
  35. Su, J., Zhou, L., Xia, M. H., Xu, Y., Xiang, X. Y. and Sun, L. K. (2014) Bcl-2 family proteins are involved in the signal crosstalk between endoplasmic reticulum stress and mitochondrial dysfunction in tumor chemotherapy resistance. Biomed. Res. Int. 2014, 234370.
  36. Trachootham, D., Alexandre, J. and Huang, P. (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579-591. https://doi.org/10.1038/nrd2803
  37. Tsao, S. M., Yin, M. C. and Liu, W. H. (2007) Oxidant stress and B vitamins status in patients with non-small cell lung cancer. Nutr. Cancer 59, 8-13. https://doi.org/10.1080/01635580701365043
  38. Virag, L., Marmer, D. J. and Szabo, C. (1998) Crucial role of apopain in the peroxynitrite-induced apoptotic DNA fragmentation. Free Radic. Biol. Med. 25, 1075-1082. https://doi.org/10.1016/S0891-5849(98)00139-7
  39. Wong, W. W. and Puthalakath, H. (2008) Bcl-2 family proteins: the sentinels of the mitochondrial apoptosis pathway. IUBMB Life 60, 390-397. https://doi.org/10.1002/iub.51

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