Skip to main content
SpringerLink
Log in

Nanoencapsulation of Docetaxel Induces Concurrent Apoptosis and Necroptosis in Human Oral Cancer Cells (SCC-9) via TNF-α/RIP1/RIP3 Pathway

  • Original Research Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

Human oral squamous cell carcinoma is the sixth most frequent malignant cancer, with an unacceptably high death rate that affects people's health. Albeit, there are several clinical approaches for diagnosing and treating oral cancer they are still far from ideal. We previously synthesised and characterised the docetaxel nanoformulation (PLGA-Dtx) and discovered that docetaxel nanoencapsulation may suppress oral cancer cells. The goal of this study was to figure out the mechanism involved in the suppression of oral cancer cell proliferation. We discovered that PLGA-Dtx inhibited SCC-9 cell growth considerably as compared to free docetaxel (Dtx), and that the viability of SCC-9 cells treated with PLGA-Dtx was decreased dose-dependently. MTT assay showed that PLGA-Dtx selectively inhibited the growth of PBMCs from oral cancer patients while sparing PBMCs from normal healthy controls. Further, flow cytometry analysis showed that PLGA-Dtx induced apoptosis and necroptosis in SCC-9 cells. G2/M cell cycle arrest has been confirmed on exposure of PLGA-Dtx for 24 h in SCC-9 cells. Interestingly, western blot investigation found that PLGA-Dtx increased the amounts of necroptic proteins and apoptosis-related proteins more efficiently than Dtx. Furthermore, PLGA-Dtx was more effective in terms of ROS generation, and mitochondrial membrane potential depletion. Pretreatment with necroptosis inhibitor Nec-1 efficiently reversed the ROS production and further recover MMP caused by PLGA-Dtx. Overall, this study revealed a mechanistic model of therapeutic response for PLGA-Dtx in SCC-9 cells and proposed its potency by inducing cell death via activation of concurrent apoptosis and necroptosis in SCC-9 cells via TNF-α/RIP1/RIP3 and caspase-dependent pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of Data and Material

Not applicable.

Code Availability

Not applicable.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol. 2015;8:11884.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou J, Kang Y, Chen L, Wang H, Liu J, Zeng S, et al. The drug-resistance mechanisms of five platinum-based antitumor agents. Front Pharmacol. 2020;11:343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ketabat F, Pundir M, Mohabatpour F, Lobanova L, Koutsopoulos S, Hadjiiski L, et al. Controlled drug delivery systems for oral cancer treatment—current status and future perspectives. Pharmaceutics. 2019;11:302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, et al. Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol. 2015;35:S78-103.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol. 2018;16:71.

    Article  Google Scholar 

  7. Zeng Q, Ma X, Song Y, Chen Q, Jiao Q, Zhou L. Targeting regulated cell death in tumor nanomedicines. Theranostics. 2022;12:817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sonkusre P, Cameotra SS. Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation. J Nanobiotechnol. 2017;15:43.

    Article  Google Scholar 

  9. Sanpui P, Chattopadhyay A, Ghosh SS. Induction of apoptosis in cancer cells at low silver nanoparticle concentrations using chitosan nanocarrier. ACS Appl Mater Interfaces. 2011;3:218–28.

    Article  CAS  PubMed  Google Scholar 

  10. Nehmé A, Varadarajan P, Sellakumar G, Gerhold M, Niedner H, Zhang Q, et al. Modulation of docetaxel-induced apoptosis and cell cycle arrest by all-trans retinoic acid in prostate cancer cells. Br J Cancer. 2001;84:1571–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:1–14. https://doi.org/10.1186/1756-9966-30-87.

    Article  CAS  Google Scholar 

  12. Green DR, Llambi F. Cell Death Signaling. Cold Spring Harb Perspect Biol. 2015;7. Available from: /pmc/articles/PMC4665079/

  13. Vanden BT, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 2014;15:135–47.

    Article  Google Scholar 

  14. Tang D, Kang R, Vanden BT, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gupta P, Singh M, Kumar R, Belz J, Shanker R, Dwivedi PD, et al. Synthesis and in vitro studies of PLGA-DTX nanoconjugate as potential drug delivery vehicle for oral cancer. Int J Nanomed. 2018;13:67.

    Article  CAS  Google Scholar 

  16. Hernández-Vargas H, Palacios J, Moreno-Bueno G. Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis. Oncogene. 2007;26:2902–13.

    Article  PubMed  Google Scholar 

  17. Mediavilla-Varela M, Pacheco FJ, Almaguel F, Perez J, Sahakian E, Daniels TR, et al. Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Mol Cancer. 2009;8:68.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wu YT, Tan HL, Huang Q, Sun XJ, Zhu X, Shen HM. zVAD-induced necroptosis in L929 cells depends on autocrine production of TNFα mediated by the PKC–MAPKs–AP-1 pathway. Cell Death Differ. 2011;18(1):26–37.

    Article  CAS  PubMed  Google Scholar 

  19. Dhuriya YK, Sharma D. Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation. 2018;15(1):1–9. https://doi.org/10.1186/s12974-018-1235-0.

    Article  CAS  Google Scholar 

  20. Chen D, Yu J, Zhang L. Necroptosis: an alternative cell death program defending against cancer. Biochim Biophys Acta. 2016;1865:228.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Antonarakis ES, Armstrong AJ. Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2011;14(3):192–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Da Rocha MCO, Da Silva PB, Radicchi MA, Andrade BYG, De Oliveira JV, Venus T, et al. Docetaxel-loaded solid lipid nanoparticles prevent tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells. J Nanobiotechnol. 2020;18:1–20. https://doi.org/10.1186/s12951-020-00604-7.

    Article  CAS  Google Scholar 

  23. Yuan Q, Han J, Cong W, Ge Y, Ma D, Dai Z, et al. Docetaxel-loaded solid lipid nanoparticles suppress breast cancer cells growth with reduced myelosuppression toxicity. Int J Nanomed. 2014;9:4829.

    Google Scholar 

  24. Yuan SJ, Xu YH, Wang C, An HC, Xu HZ, Li K, et al. Doxorubicin-polyglycerol-nanodiamond conjugate is a cytostatic agent that evades chemoresistance and reverses cancer-induced immunosuppression in triple-negative breast cancer. J Nanobiotechnology. 2019;17:110.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Srivastava A, Amreddy N, Babu A, Panneerselvam J, Mehta M, Muralidharan R, et al. Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci Rep. 2016;6(1):1–15.

    Article  Google Scholar 

  26. Mann J, Yang N, Montpetit R, Kirschenman R, Lemieux H, Goping IS. BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis. Sci Rep 2020;10. Available from: /pmc/articles/PMC6962214/

  27. Lee GY, Mubasher M, Mckenzie TS, Schmitt NC, Sebelik ME, Flanagan CE, et al. Assessment of a nano-docetaxel combined treatment for head and neck cancer. Onco. 2021;1:83–94.

    Article  Google Scholar 

  28. Feng X, Xiong X, Ma S. Docetaxel-loaded novel nano-platform for synergistic therapy of non-small cell lung cancer. Front Pharmacol. 2022;13:230.

    Article  Google Scholar 

  29. Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, et al. RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med. 2019;44:771.

    PubMed  PubMed Central  Google Scholar 

  30. Kaokaen P, Chaicharoenaudomrung N, Kunhorm P, Mesil K, Binlateh T, Noisa P, et al. Nanoencapsulation of cordycepin induces switching from necroptosis to apoptosis in human oral cancer cells (HSC-4) through inhibition of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and autophagy modulation. Natural Product Commun. 2022. https://doi.org/10.1177/1934578X221074838.

    Article  Google Scholar 

  31. Wilhelmi V, Fischer U, Weighardt H, Schulze-Osthoff K, Nickel C, Stahlmecke B, et al. Zinc oxide nanoparticles induce necrosis and apoptosis in macrophages in a p47phox- and Nrf2-independent manner. PLoS ONE. 2013;8:e65704. https://doi.org/10.1371/journal.pone.0065704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, et al. ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020;52(2):192–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reczek CR, Chandel NS. The two faces of reactive oxygen species in cancer. Annu Rev Cancer Biol. 2017;1:79–98.

    Article  Google Scholar 

  34. Xian D, Lai R, Song J, Xiong X, Zhong J. Emerging Perspective: Role of Increased ROS and Redox Imbalance in Skin Carcinogenesis. Oxid Med Cell Longev 2019;2019. Available from: /pmc/articles/PMC6766104/

  35. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu B, Gong X, Wang ZQ, Ding Y, Wang C, Luo TF, et al. Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. Acta Pharmacol Sin. 2017;38(11):1543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schenk B, Fulda S. Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death. Oncogene. 2015;34(47):5796–806.

    Article  CAS  PubMed  Google Scholar 

  38. Morgan MJ, Liu ZG. Reactive oxygen species in TNFα-induced signaling and cell death. Mol Cells. 2010;30:1.

    Article  CAS  PubMed  Google Scholar 

  39. Sun W, Wu X, Gao H, Yu J, Zhao W, Lu JJ, et al. Cytosolic calcium mediates RIP1/RIP3 complex-dependent necroptosis through JNK activation and mitochondrial ROS production in human colon cancer cells. Free Radic Biol Med Pergamon. 2017;108:433–44.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are sincerely thankful to Dr. P. D. Dwivedi, Retired Senior Principal Scientist, CSIR-Indian Institute of Toxicology Research,Lucknow for providing guidance and facility for laboratory experiments.

Funding

This work was supported by Council of Scientific & Industrial Research (CSIR), India [No. 31/29(262)/2017-EMR-I, Fellowship to PG].

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine, King George’s Medical University, Lucknow, Uttar Pradesh, 226003, India

    Parul Gupta, Ajay Kumar Verma, Surya Kant & Anuj Kumar Pandey

  2. Department of Pharmacology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India

    Arpita Singh

  3. Department of Otorhinolaryngology & Head Neck Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, 226003, India

    Anupam Mishra

  4. Flow Cytometry Facility, Central Instrumentation Facility, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India

    Puneet Khare

  5. Department of Pulmonary & Critical Care Medicine, King George’s Medical University, Lucknow, Uttar Pradesh, 226003, India

    Ved Prakash

Authors
  1. Parul Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arpita Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ajay Kumar Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Surya Kant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anuj Kumar Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anupam Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Puneet Khare
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ved Prakash
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: PG, AKV. Data analysis: PG, AKV, AKP, AS, PK. Funding: PG. Investigation: PG, AKV, AS, AKP, SK, PK,VP. Experimental studies: PG, VK, AKP, AM, AKV. Validation: PG, AKV, AKP, AS, AM, PK, VP. Manuscript writing & original draft: PG, AKP, AKV, AS. Writing, review & editing: PG, AKV, AS, AKP, SK, AM, VK, VP.

Corresponding author

Correspondence to Ajay Kumar Verma.

Ethics declarations

Conflict of interest

Authors declare no competing interest.

Ethics Approval

Study protocol was approved by Institutional Ethics Committee of the institution. Additionally, study was performed in accordance of approved protocol.

Consent to Participate

Informed written consent was taken from all the participants prior to enrolling in the study.

Consent for Publication

Written consent was obtained from all the persons prior to publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gupta, P., Singh, A., Verma, A.K. et al. Nanoencapsulation of Docetaxel Induces Concurrent Apoptosis and Necroptosis in Human Oral Cancer Cells (SCC-9) via TNF-α/RIP1/RIP3 Pathway. Ind J Clin Biochem 38, 351–360 (2023). https://doi.org/10.1007/s12291-022-01055-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-022-01055-7

Keywords

Search

Navigation