Skip to main content

Advertisement

SpringerLink
Log in

Cobalt (III) complex exerts anti-cancer effects on T cell lymphoma through induction of cell cycle arrest and promotion of apoptosis

  • Research article
  • Published:
DARU Journal of Pharmaceutical Sciences Aims and scope Submit manuscript

Abstract

Purpose

Cobalt-based compounds are emerging as a non-platinum-based anti-cancer effective therapeutic agent. However, there is a limited study regarding the therapeutic efficacy of Cobalt-based drugs against Non-Hodgkin’s Lymphoma (NHLs) such as T cell lymphoma. Therefore, in the present study we investigated the anti-tumor role of cobalt(III) complex [Co(ptsm)NH3(o-phen)]·CH3OH on Dalton’s Lymphoma (DL) cells.

Materials and methods

Cytotoxicity of the cobalt complex was estimated by MTT assay. Analysis of mitochondrial membrane potential, cell cycle and Reactive oxygen species (ROS) generation, and Annexin V/PI staining was done by Flow cytometry, while AO/EtBr staining by fluorescence microscopy in cobalt complex treated DL cell. Expression of cell cycle and apoptosis regulatory protein was analyzed by Western blotting. In addition, in vivo study of the cobalt complex was evaluated in well-established DL bearing mice by monitoring physiological parameters and mean survival time.

Results

Our study showed that cobalt complex triggered apoptosis and induced cell cycle arrest in DL cells. Furthermore, this also decreased mitochondrial membrane potential and increased intracellular ROS generation in cancer cells. In addition, changed expression of cell cycle and apoptosis regulatory protein was found with enhanced activity of caspase-3 and 9 in the treated cells. Additionally, administration of cobalt complex showed a significant increase in the survivability of tumor-bearing host, which was accomplished by decreasing physiological parameters.

Conclusion

Taken together, these data revealed anti-tumor potential of cobalt complex against DL cells through cell cycle arrest and mitochondrial-dependent apoptosis. Henceforth, cobalt-based drugs could be a new generation therapeutic drug to treat hematological malignancies.

Graphical abstract

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

AO:

Acridine orange

DAPI:

4′, 6-diamidino-2-phenylindole

DL:

Dalton’s Lymphoma

DMSO:

Dimethyl sulphoxide

EtBr:

Ethidium Bromide

FACS:

Fluorescence-activated cell sorting

H2DCF-DA:

2′, 7′-Dichlorofluorescin diacetate

HT-29:

Human colon cancer

IC50 :

Concentration for 50% growth inhibition

MMP:

Mitochondrial Membrane Potential

MTT:

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

NHL:

Non-Hodgkin Lymphoma

NAC:

N-acetyl cysteine

PARP:

Poly ADP ribose polymerase

PBS:

Phosphate buffered saline

RPMI:

Roswell Park Memorial Institute

U-87:

Glioblastoma cells

References

  1. Koiri RK, Mehrotra A, Trigun SK. Dalton’s lymphoma as a murine model for understanding the progression and development of T-cell lymphoma and its role in drug discovery. International Journal of Immunotherapy and Cancer Research. 2017;3(1):001–6.

    Google Scholar 

  2. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.

    Article  CAS  Google Scholar 

  3. Ndagi U, Mhlongo N, Soliman ME. Metal complexes in cancer therapy–an update from drug design perspective. Drug Design, Development and Therapy. 2017;11:599.

    Article  CAS  Google Scholar 

  4. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.

    Article  CAS  Google Scholar 

  5. Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK. Antitumour metal compounds: more than theme and variations. Dalton Trans. 2008;2:183–94.

    Article  Google Scholar 

  6. Bratsos I, Jedner S, Gianferrara T, Alessio E. Ruthenium anticancer compounds: challenges and expectations. CHIMIA International Journal for Chemistry. 2007;61(11):692–7.

    Article  CAS  Google Scholar 

  7. Lu QB, Zhang QR, Ou N, Wang CR, Warrington J. In vitro and in vivo studies of non-platinum-based halogenated compounds as potent antitumor agents for natural targeted chemotherapy of cancers. E Bio Medicine. 2015;2(6):544–53.

    Google Scholar 

  8. Munteanu CR, Suntharalingam K. Advances in cobalt complexes as anticancer agents. Dalton Trans. 2015;44(31):13796–808.

    Article  CAS  Google Scholar 

  9. Gowdhami B, Manojkumar Y, Vimala RT, Ramya V, Karthiyayini B, Kadalmani B, Akbarsha MA. Cytotoxic cobalt (III) Schiff base complexes: in vitro anti-proliferative, oxidative stress and gene expression studies in human breast and lung cancer cells. BioMetals. 2021:1–9.

  10. Law BY, Qu YQ, Mok SW, Liu H, Zeng W, Han Y, Gordillo-Martinez F, Chan WK, Wong KM, Wong VK. New perspectives of cobalt tris (bipyridine) system: anti-cancer effect and its collateral sensitivity towards multidrug-resistant (MDR) cancers. Oncotarget. 2017;8(33):55003.

    Article  Google Scholar 

  11. Ott I, Kircher B, Gust R. Investigations on the effects of cobalt-alkyne complexes on leukemia and lymphoma cells: cytotoxicity and cellular uptake. J Inorg Biochem. 2004;98(3):485–9.

    Article  CAS  Google Scholar 

  12. Hopff SM, Onambele LA, Brandenburg M, Berkessel A, Prokop A. Discovery of a cobalt (III) salen complex that induces apoptosis in Burkitt like lymphoma and leukemia cells, overcoming multidrug resistance in vitro. Bioorg Chem. 2020;104:104193.

    Article  CAS  Google Scholar 

  13. Ghandhi LH. Cobalt picolinamide complexes as potential anti-cancer agents. Doctoral dissertation, University of Leeds, 2017.

  14. Nath P, Bharty MK, Dani RK, Tomar MS, Acharya A. Mn (II), co (III), Ni (II), cd (II) and cu (II) complexes of 2-Thenoyltrifluoroacetone: syntheses, structures, photoluminescence, thermal, electrochemical and antitumor studies on Dalton's lymphoma cells. Chemistry Select. 2017;13(32):10449–58.

    Google Scholar 

  15. Gharbavi M, Johari B, Eslami SS, Mousazadeh N, Sharafi A. Cholesterol-conjugated bovine serum albumin nanoparticles as a tamoxifen tumor-targeted delivery system. Cell Biol Int. 2020;44(12):2485–98.

    Article  CAS  Google Scholar 

  16. Rastogi RP, Singh SP, Häder DP, Sinha RP. Detection of reactive oxygen species (ROS) by the oxidant-sensing probe 2′, 7′-dichlorodihydrofluorescein diacetate in the cyanobacterium Anabaena variabilis PCC 7937. Biochem Biophys Res Commun. 2010;397(3):603–7.

    Article  CAS  Google Scholar 

  17. Singh RK, Verma PK, Kumar S, Shukla A, Kumar N, Kumar S, Acharya A. Evidence that PKCα inhibition in Dalton's lymphoma cells augments cell cycle arrest and mitochondrial-dependent apoptosis. Leuk Res. 2022;106772.

  18. Gharbavi M, Johari B, Rismani E, Mousazadeh N, Taromchi AH, Sharafi A. NANOG decoy oligodeoxynucleotide–encapsulated niosomes nanocarriers: a promising approach to suppress the metastatic properties of U87 human glioblastoma multiforme cells. ACS Chem Neurosci. 2020;11(24):4499–515.

    Article  CAS  Google Scholar 

  19. Verma PK, Gond MK, Bharty MK, Acharya A. Mitochondrial pathway mediated apoptosis and cell cycle arrest triggered by cobalt (III) complex in Dalton’s lymphoma cells. Journal of Applied Pharmaceutical Science. 2021;11(10):007–15.

    CAS  Google Scholar 

  20. Liu LH, Shi RJ, Chen ZC. Paeonol exerts anti-tumor activity against colorectal cancer cells by inducing G0/G1 phase arrest and cell apoptosis via inhibiting the Wnt/β-catenin signaling pathway. Int J Mol Med. 2020;46(2):675–84.

    Article  Google Scholar 

  21. Singh RK, Verma PK, Kumar A, Kumar S, Acharya A. Achyranthes aspera L leaf extract induced anticancer effects on Dalton's Lymphoma via regulation of PKCα signaling pathway and mitochondrial apoptosis. Journal of Ethnopharmacology. 2021;274:114060.

    Article  CAS  Google Scholar 

  22. Akindele AJ, Wani ZA, Sharma S, Mahajan G, Satti NK, Adeyemi OO, Mondhe DM, Saxena AK. In vitro and in vivo anticancer activity of root extracts of Sansevieria liberica Gerome and Labroy (Agavaceae). Evid Based Complement Alternat Med. 2015;2015.

  23. Baracca A, Sgarbi G, Solaini G, Lenaz G. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F0 during ATP synthesis. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2003;1606(1–3):137–46.

    Article  CAS  Google Scholar 

  24. Yi M, Parthiban P, Hwang J, Zhang X, Jeong H, Park DH, Kim DK. Effect of a bispidinone analog on mitochondria-mediated apoptosis in HeLa cells. Int J Oncol. 2014;44(1):327–35.

    Article  CAS  Google Scholar 

  25. Minard-Colin V, Brugières L, Reiter A, Cairo MS, Gross TG, Woessmann W, Burkhardt B, Sandlund JT, Williams D, Pillon M, Horibe K. Non-Hodgkin lymphoma in children and adolescents: progress through effective collaboration, current knowledge, and challenges ahead. J Clin Oncol. 2015;33(27):2963.

    Article  CAS  Google Scholar 

  26. Armitage JO, Gascoyne RD, Lunning MA, Cavalli F. Non-hodgkin lymphoma. Lancet. 2017;390(10091):298–310.

    Article  Google Scholar 

  27. Thamilarasan V, Sengottuvelan N, Sudha A, Srinivasan P, Chakkaravarthi G. Cobalt (III) complexes as potential anticancer agents: physicochemical, structural, cytotoxic activity and DNA/protein interactions. J Photochem Photobiol B Biol. 2016;162:558–69.

    Article  CAS  Google Scholar 

  28. Al-Naeeb AB, Ajithkumar T, Behan S, Hodson DJ. Non-Hodgkin lymphoma. BMJ. 2018;362.

  29. Diumenjo MC, Abriata G, Forman D, Sierra MS. The burden of non-Hodgkin lymphoma in central and South America. Cancer Epidemiol. 2016;44:S168–77.

    Article  Google Scholar 

  30. Alghamdi NJ, Balaraman L, Emhoff KA, Salem AM, Wei R, Zhou A, Boyd WC. Cobalt (II) diphenylazodioxide complexes induce apoptosis in SK-HEP-1 cells. ACS Omega. 2019;4(11):14503–10.

    Article  CAS  Google Scholar 

  31. Lee SH, Meng XW, Flatten KS, Loegering DA, Kaufmann SH. Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm. Cell Death & Differentiation. 2013;20(1):64–76.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Li L, Wong YS, Chen T, Fan C, Zheng W. Ruthenium complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers. Dalton Trans. 2012;41(4):1138–41.

    Article  CAS  Google Scholar 

  34. Chipuk JE, Green DR. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2008;18(4):157–64.

    Article  CAS  Google Scholar 

  35. Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, Varol M, Jain A, Khan M, Sethi G. Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules. 2019;9(11):735.

    Article  CAS  Google Scholar 

  36. Samanta A, Ravindran G, Sarkar A. Quinacrine causes apoptosis in human cancer cell lines through caspase-mediated pathway and regulation of small-GTPase. J Biosci. 2020;45(1):1–8.

    Article  Google Scholar 

  37. González-Gironès DM, Moncunill-Massaguer C, Iglesias-Serret D, Cosialls AM, Pérez-Perarnau A, Palmeri CM, Rubio-Patiño C, Villunger A, Pons G, Gil J. AICAR induces Bax/Bak-dependent apoptosis through upregulation of the BH3-only proteins Bim and Noxa in mouse embryonic fibroblasts. Apoptosis. 2013;18(8):1008–16.

    Article  Google Scholar 

  38. Li X, Qiu Z, Jin Q, Chen G, Guo M. Cell cycle arrest and apoptosis in HT-29 cells induced by dichloromethane fraction from Toddalia asiatica (L.) Lam. Frontiers in Pharmacology. 2018;9:629.

    Article  Google Scholar 

  39. Meikrantz W, Schlegel R. Apoptosis and the cell cycle. J Cell Biochem. 1995;58(2):160–74.

    Article  CAS  Google Scholar 

  40. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B. 14-3-3σ is a p53-regulated inhibitor of G2/M progression. Mol Cell. 1997;1(1):3–11.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Authors are thankful to Dr. Manoj Kumar Bharty, Department of Chemistry, Banaras Hindu University, Varanasi for providing cobalt (III) complex. We also acknowledge Interdisciplinary School of Life Science, Banaras Hindu University, Varanasi for providing Fluorescence microscopy and Flow cytometry facilities. PKV is a recipient of Senior Research Fellowship from the Indian Council of Medical Research (ICMR-SRF/45/73/2018/PHA/BMS), India. The work was supported by the grants received from Banaras Hindu University and DST- SERB (P-07/705), government of India to corresponding author.

Availability of data and materials

Available upon the request.

Author information

Authors and Affiliations

  1. Immunology Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Praveen Kumar Verma, Rishi Kant Singh, Sandeep Kumar, Alok Shukla, Sanjay Kumar & Arbind Acharya

  2. Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Mannu Kumar Gond & Manoj Kumar Bharty

Authors
  1. Praveen Kumar Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rishi Kant Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alok Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sanjay Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mannu Kumar Gond
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manoj Kumar Bharty
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arbind Acharya
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The research work presented in the manuscript is a part of Ph.D. thesis of PKV. PKV and AA designed the study. PKV, RKS, SK and AS performed all the experiments. PKV, RKS and AA wrote the manuscript and PKV, RKS, SK and AA critically revised corrected and modified the manuscript. MKG and MKB provided cobalt complex.

Corresponding author

Correspondence to Arbind Acharya.

Ethics declarations

Ethics approval

Ethical approval was taken from Institutional Animal Ethics committee of the Department of Zoology, Banaras Hindu University (BHU), Varanasi, India (Reference No. BHU/DoZ/IAEC/ 2018–19/51).

Informed consent

For this type of study formal consent is not required.

Consent for publication

Not applicable.

Competing interests

The Authors declare that there is no conflict of interest among the authors.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verma, P.K., Singh, R.K., Kumar, S. et al. Cobalt (III) complex exerts anti-cancer effects on T cell lymphoma through induction of cell cycle arrest and promotion of apoptosis. DARU J Pharm Sci 30, 127–138 (2022). https://doi.org/10.1007/s40199-022-00439-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40199-022-00439-7

Keywords

Search

Navigation