ALK and ERBB2 Protein Inhibition is Involved in the Prevention of Lung Cancer Development by Vincamine


Цитировать

Полный текст

Аннотация

Background: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer.

Objective: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line.

Methods: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer.

Results: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dosedependent (0-500 µM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 µΜ. The wound-healing assay showed that vincamine treatment (150 and 300 µM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells.

Conclusion: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.

Об авторах

Aarti Verma

Department of Pharmacology, Central University of Punjab

Email: info@benthamscience.net

Poonam Yadav

Department of Pharmacology, Central University of Punjab

Email: info@benthamscience.net

Sonu Rajput

Department of Pharmacology, Central University of Punjab

Email: info@benthamscience.net

Saloni Verma

Department of Pharmacology, Central University of Punjab

Email: info@benthamscience.net

Sahil Arora

Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab

Email: info@benthamscience.net

Raj Kumar

Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab

Email: info@benthamscience.net

Jasvinder Bhatti

Department of Human Genetics and Molecular Medicine, Central University of Punjab

Email: info@benthamscience.net

Amit Khurana

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital

Email: info@benthamscience.net

Umashanker Navik

Department of Pharmacology, Central University of Punjab

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. WHO. Cancer 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer
  2. Zheng, M. Classification and pathology of lung cancer. Surg. Oncol. Clin., 2016, 25(3), 447-468. PMID: 27261908
  3. Amaani, R.; Dwira, S. In Journal of Physics: Conference Series; IOP Publishing, Bristol, UK, 2018, 1073, p. 032042.
  4. Surya, K.D. Fundamentals of Cancer Detection, Treatment, and Prevention. In: Pharmacology & Pharmaceutical Medicine; Springer Berlin, Heidelberg, pp. 536.
  5. Brambilla, E.; Gazdar, A. Pathogenesis of lung cancer signalling pathways: Roadmap for therapies. Eur. Respir. J., 2009, 33(6), 1485-1497. doi: 10.1183/09031936.00014009 PMID: 19483050
  6. Ou, S.H.I.; Shirai, K. Anaplastic lymphoma kinase (ALK) signaling in lung cancer. Adv. Exp. Med. Biol., 2016, 893, 179-187. doi: 10.1007/978-3-319-24223-1_9 PMID: 26667344
  7. Dhyani, P.; Quispe, C.; Sharma, E.; Bahukhandi, A.; Sati, P.; Attri, D.C.; Szopa, A.; Sharifi-Rad, J.; Docea, A.O.; Mardare, I.; Calina, D.; Cho, W.C. Anti-cancer potential of alkaloids: A key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell Int., 2022, 22(1), 206. doi: 10.1186/s12935-022-02624-9 PMID: 35655306
  8. Fandy, T.E.; Abdallah, I.; Khayat, M.; Colby, D.A.; Hassan, H.E. In vitro characterization of transport and metabolism of the alkaloids: Vincamine, vinpocetine and eburnamonine. Cancer Chemother. Pharmacol., 2016, 77(2), 259-267. doi: 10.1007/s00280-015-2924-3 PMID: 26666648
  9. Patangrao, R.A.; Kumar, B.A.; Kumar, B.K.; Mekala, L.; Mahesh, K.J.; Neeradi, D.; Durga, V.H.D.; Gadige, A.; Khurana, A. Vincamine, an active constituent of Vinca rosea ameliorates experimentally induced acute lung injury in Swiss albino mice through modulation of Nrf-2/NF-κB signaling cascade. Int. Immunopharmacol., 2022, 108, 108773. doi: 10.1016/j.intimp.2022.108773 PMID: 35453074
  10. Al-Rashed, S.; Baker, A.; Ahmad, S.S.; Syed, A.; Bahkali, A.H.; Elgorban, A.M.; Khan, M.S. Vincamine, a safe natural alkaloid, represents a novel anti-cancer agentt. Bioorg. Chem., 2021, 107, 104626. doi: 10.1016/j.bioorg.2021.104626 PMID: 33450545
  11. Xie, B.; Lu, H.; Xu, J.; Luo, H.; Hu, Y.; Chen, Y.; Geng, Q.; Song, X.J.J.B.S. Targets of hydroxychloroquine in the treatment of rheumatoid arthritis. A network pharmacology study. Joint Bone Spine, 2021, 88(2), 105099.
  12. Arora, S.; Joshi, G.; Kalra, S.; Wani, A.A.; Bharatam, P.V.; Kumar, P.; Kumar, R. Knoevenagel/tandem knoevenagel and michael adducts of cyclohexane-1, 3-dione and aryl aldehydes: synthesis, DFT studies, xanthine oxidase inhibitory potential, and molecular modeling. ACS Omega, 2019, 4(3), 4604-4614. doi: 10.1021/acsomega.8b03060
  13. Tominaga, H.; Ishiyama, M.; Ohseto, F.; Sasamoto, K.; Hamamoto, T.; Suzuki, K.; Watanabe, M.J.A.C. A water-soluble tetrazolium salt useful for colorimetric cell viability assay. Anal. Commun., 1999, 36, 47-50. doi: 10.1039/a809656b
  14. Li, F.F.; Zhang, H.; Li, J.J.; Cao, Y.N.; Dong, X.; Gao, C.J.M.M.R. Interaction with adipocytes induces lung adenocarcinoma A549 cell migration and tumor growth. Euro. Comm. Invent. NAMs Respirat. Tract. dis., 2018, 18(2), 1973-1980. doi: 10.3892/mmr.2018.9226
  15. Shrivastava, S.; Jeengar, M.K.; Reddy, V.S.; Reddy, G.B.; Naidu, V.J.E. Anti-cancer effect of celastrol on human triple negative breast cancer: Possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways. Exp. Mol. Pathol., 2015, 98(3), 313-327.
  16. Kaja, S.; Payne, A.J.; Naumchuk, Y.; Levy, D.; Zaidi, D.H.; Altman, A.M.; Nawazish, S.; Ghuman, J.K.; Gerdes, B.C.; Moore, M.A.J.E.r. Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. Exp. Eye Res., 2015, 138, 159-166. doi: 10.1016/j.exer.2015.05.023
  17. Fernando, D.; Adhikari, A.; Nanayakkara, C.; de Silva, E.D.; Wijesundera, R.; Soysa, P.J.B.c. Cytotoxic effects of ergone, a compound isolated from Fulviformes fastuosus. BMC Complement. Altern. Med., 2016, 16(1), 484.
  18. Mortezaee, K.; Salehi, E.; Mirtavoos-mahyari, H.; Motevaseli, E.; Najafi, M.; Farhood, B.; Rosengren, R.J.; Sahebkar, A. Mechanisms of apoptosis modulation by curcumin: Implications for cancer therapy. J. Cell. Physiol., 2019, 234(8), 12537-12550. doi: 10.1002/jcp.28122 PMID: 30623450
  19. Buja, L.M.; Eigenbrodt, M.L.; Eigenbrodt, E.H. Apoptosis and necrosis. Basic types and mechanisms of cell death. Arch. Pathol. Lab. Med., 1993, 117(12), 1208-1214. PMID: 8250690
  20. Dey, P.; Kundu, A.; Chakraborty, H.J.; Kar, B.; Choi, W.S.; Lee, B.M.; Bhakta, T.; Atanasov, A.G.; Kim, H.S. Therapeutic value of steroidal alkaloids in cancer: Current trends and future perspectives. Int. J. Cancer, 2019, 145(7), 1731-1744. doi: 10.1002/ijc.31965 PMID: 30387881
  21. Woods, J.R.; Riofski, M.V.; Zheng, M.M.; O'Banion, M.A.; Mo, H.; Kirshner, J.; Colby, D.A. Synthesis of 15-methylene-eburnamonine from (+)-vincamine, evaluation of anti-cancer activity, and investigation of mechanism of action by quantitative NMR. Bioorg. Med. Chem. Lett., 2013, 23(21), 5865-5869. doi: 10.1016/j.bmcl.2013.08.095 PMID: 24055047
  22. Sprumont, P.; Lintermans, J. Autoradiographic evidence for passage of vincamine through the blood-brain barrier. Arch. Int. Pharmacodyn. Ther., 1979, 237(1), 42-48. PMID: 485685
  23. Sullivan, I.; Planchard, D. ALK inhibitors in non-small cell lung cancer: The latest evidence and developments. Ther. Adv. Med. Oncol., 2016, 8(1), 32-47. doi: 10.1177/1758834015617355 PMID: 26753004
  24. Arbour, K.C.; Riely, G.J. Diagnosis and treatment of anaplastic lymphoma kinase–positive non–small cell lung cancer. Hematol. Oncol. Clin. North Am., 2017, 31(1), 101-111. doi: 10.1016/j.hoc.2016.08.012 PMID: 27912826
  25. Zeng, J.; Ma, W.; Young, R.B.; Li, T. Targeting HER2 genomic alterations in non-small cell lung cancer. J. Nat. Cancer Center, 2021, 1(2), 58-73. doi: 10.1016/j.jncc.2021.04.001
  26. Yu, X.; Ji, X.; Su, C. HER2-altered non-small cell lung cancer: Biology; Clinicopathologic features, and emerging therapies. Front. Oncol., 2022, 12, 860313.
  27. Freitas, J.T.; Jozic, I.; Bedogni, B. Wound healing assay for melanoma cell migration. Methods Mol. Biol., 2021, 2265, 65-71. doi: 10.1007/978-1-0716-1205-7_4 PMID: 33704705
  28. Yang, S.; Li, X.; Dou, H.; Hu, Y.; Che, C.; Xu, D. Sesamin induces A549 cell mitophagy and mitochondrial apoptosis via a reactive oxygen species-mediated reduction in mitochondrial membrane potential. Korean J. Physiol. Pharmacol., 2020, 24(3), 223-232. doi: 10.4196/kjpp.2020.24.3.223

Дополнительные файлы

Доп. файлы
Действие
1. JATS XML
Скачать

© Bentham Science Publishers, 2023