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Evaluation of the Antitumor Activity of Omipalisib, a PI3K/AKT/MTOR Pathway Inhibitor, on Burkitt Lymphoma Cell Line

Year 2023, Volume: 44 Issue: 4, 635 - 639, 28.12.2023

Zekeriya Keskin , Fatih Yulak , Hatice Terzi , Merve İnanır

https://doi.org/10.17776/csj.1344535

Abstract

There are many challenges in the treatment of Burkitt lymphoma, especially in immunocompromised individuals, elderly patients, and patients with relapsed or refractory disease. Therefore, there is a need for new and less toxic therapeutic agents. The aim of this study was to determine the antitumoral activity of omipalisib, a PI3K/AKT/mTOR pathway inhibitor, in the Burkitt lymphoma. Raji cell line was used in the study. Omipalisib was administered to the cell line and then the cytotoxic effect of omipalisib on Raji cells was evaluated by the XTT test. The IC50 value was calculated according to the results of the XTT test. Apoptosis and cell cycle experiments were studied with the calculated IC50 value. The flow cytometric method was used to determine the effect of omipalisib on apoptosis and cell death. The results of the study showed a statistically significant cytotoxic effect of increasing concentrations of omipalisib on Raji cells. The apoptosis experiment performed revealed that omipalisib strongly induced apoptosis. The cell cycle experiment showed that omipalisib stimulated the cell cycle arrest at the G0/G1 phase. It was concluded that omipalisib exhibited antitumoral activity on Burkitt lymphoma cells with its cytotoxic effect and induced apoptosis and cell cycle arrest. Considering this effect, targeting the PI3K/AKT/mTOR pathway with omipalisib can be a new treatment option.

Keywords

Apoptosis Cell Cycle Omipalisib Raji Cells XTT

Supporting Institution

cübap

Project Number

T-896

Thanks

This study was supported by Sivas Cumhuriyet University Scientific Research Projects (CUBAP) with the project number of T-896. The authors thank Sivas Cumhuriyet University Medical Faculty Research Center-CUTFAM for supplying the required facilities for the conduct of this study.

References

  • [1] Saleh K., Michot J. M., Camara C.V., Vassetsky Y., Ribrag V., Burkitt and Burkitt-Like Lymphomas: a Systematic Review, Curr. Oncol. Rep., 22(4) (2020) 33.
  • [2] Ishizawa K., JSH Practical Guidelines for Hematological Malignancies, 2018: II. Lymphoma-6. Burkitt Lymphoma (BL), Int. J. Hematol., 110 (3) (2019) 265–271.
  • [3] Linch D. C., Burkitt Lymphoma in Adults, Br. J. Haematol., 156(6) (2012) 693–703.
  • [4] Dunleavy K., Little R. F., Wilson W. H., Update on Burkitt Lymphoma, Hematol. Oncol. Clin. North. Am., 30(6) (2016) 1333–1343.
  • [5] Bhatti M., Ippolito T., Mavis C., Gu J., Cairo M. S., Lim M. S., Francisco H.I., Matthew J. B., Pre-clinical Activity of Targeting the PI3K/Akt/mTOR Pathway in Burkitt Lymphoma, Oncotarget., 30(6) (2018)1333–1343.
  • [6] Markman B., Atzori F., Pérez-García J., Tabernero J., Baselga J., Status of PI3K İnhibition and Biomarker Development in Cancer Therapeutics, Ann. Oncol., 21(4) (2009) 683–691.
  • [7] Porta C., Paglino C., Mosca A., Targeting PI3K/Akt/mTOR Signaling in Cancer, Front. Oncol., 4(2014) 1-11.
  • [8] Janku F., Yap T. A., Meric B. F., Targeting the PI3K Pathway in Cancer: Are We Making Headway?, Nat. Rev. Clin. Oncol., 15(5) (2018) 273–291.
  • [9] Liu T., Sun Q., Li Q., Yang H., Zhang Y., Wang R., et al., Dual PI3K/Mtor Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma, Mol. Cancer Ther., 14 (2) (2015) 429–439.
  • [10] Knight S.D., Adams N.D., Burgess J.L., Chaudhari A.M., Darcy M.G., Donatelli C.A., Luengo J.I., Newlander K.A., Parrish C.A., Ridgers L.H., Sarpong M.A., Schmidt S.J., Van Aller G.S., Carson J.D., Diamond M.A., Elkins P.A., Gardiner C.M., Garver E., Gilbert S.A., Gontarek R.R., Jackson J.R., Kershner K.L., Luo L., Raha K., Sherk C.S., Sung C.M., Sutton D., Tummino P. J., Wegrzyn R. J., Auger K.R., Dhanak D., Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin, ACS Med. Chem. Lett., 1(1) (2010) 39–43.
  • [11] Bociek R.G., Adult Burkitt’s Lymphoma, Clin. Lymphoma.,6 (2005) 11–20.
  • [12] Zayac A.S., Olszewski A. J., Burkitt Lymphoma: Bridging the Gap Between Advances in Molecular Biology and Therapy, Leuk. Lymphom., 61(8) (2020) 1784–1796.
  • [13] Short N. J., Kantarjian H.M., Ko H., Khoury J.D., Ravandi F., Thomas D.A.,Garcia M.G., Khouri M., Cortes J. E., Wierda W.G., Verstovsek S., Estrov Z., Ferrajoli A., Thompson P. A., Pierce S.A., O'Brien S.M., Jabbour E., Outcomes of Adults with Relapsed or Refractory Burkitt and High-Grade B-cell Leukemia/Lymphoma, Am. J. Hematol., 92(6) (2017) 114–117.
  • [14] Sweetenham J. W., Pearce R., Taghipour G., Biaise D., Gisselbrecht C., Goldstone A.H., Adult Burkitt’s and Burkitt-like non-Hodgkin’s lymphoma - Outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: Results from the European group for blood and marrow transplantation, J. Clin. Oncol., 14(9) (1996) 2465–2472.
  • [15] Ippolito T, Mavis C, Gu J, Hernandez-Ilizaliturri F. J, Barth M. J. Omipalisib (GSK458), a Dual an-PI3K/mTOR Inhibitor, Exhibits in Vitro and In Vivo Activity in Chemotherapy-Sensitive and -Resistant Models of Burkitt Lymphoma, Blood., 132 (2018) 2951–2951.
  • [16] Li C, Xin P, Xiao H, Zheng Y, Huang Y, Zhu X. The dual PI3K/mTOR inhibitor NVP-BEZ235 Inhibits Proliferation and Induces Apoptosis of Burkitt Lymphoma Cell, Cancer Cell Int., 15 (2015) 1–9.
  • [17] Munster P, Aggarwal R, Hong D, Schellens J.H.M., Van Der Noll R., Specht J., Witteveen P.O., Werner T.L., Dees E.C., Bergsland E., Agarwal N., Kleha S.F., Durante M., Adams L., Smith D.A., Lampkin T.A., Morris S.R., Kurzrock R., First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies., Clin. Cancer Res., 22 (2016) 1932–1939.
  • [18] Wong K., Di Cristofano F., Ranieri M., De Martino D., Di Cristofano A., PI3K/mTOR Inhibition Potentiates and Extends Palbociclib Activity in Anaplastic Thyroid Cancer, Endocr. Relat. Cancer., 26 (2018) 425–436.
  • [19] Zhu D.S, Dong J.Y, Xu Y.Y, Zhang X.T, Fu S.B, Liu W., Omipalisib Inhibits Esophageal Squamous Cell Carcinoma Growth Through Inactivation of Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) and ERK Signaling, Med. Sci. Monit., 26( 2020) e927106.

Year 2023, Volume: 44 Issue: 4, 635 - 639, 28.12.2023

Zekeriya Keskin , Fatih Yulak , Hatice Terzi , Merve İnanır

https://doi.org/10.17776/csj.1344535

Abstract

Project Number

T-896

References

  • [1] Saleh K., Michot J. M., Camara C.V., Vassetsky Y., Ribrag V., Burkitt and Burkitt-Like Lymphomas: a Systematic Review, Curr. Oncol. Rep., 22(4) (2020) 33.
  • [2] Ishizawa K., JSH Practical Guidelines for Hematological Malignancies, 2018: II. Lymphoma-6. Burkitt Lymphoma (BL), Int. J. Hematol., 110 (3) (2019) 265–271.
  • [3] Linch D. C., Burkitt Lymphoma in Adults, Br. J. Haematol., 156(6) (2012) 693–703.
  • [4] Dunleavy K., Little R. F., Wilson W. H., Update on Burkitt Lymphoma, Hematol. Oncol. Clin. North. Am., 30(6) (2016) 1333–1343.
  • [5] Bhatti M., Ippolito T., Mavis C., Gu J., Cairo M. S., Lim M. S., Francisco H.I., Matthew J. B., Pre-clinical Activity of Targeting the PI3K/Akt/mTOR Pathway in Burkitt Lymphoma, Oncotarget., 30(6) (2018)1333–1343.
  • [6] Markman B., Atzori F., Pérez-García J., Tabernero J., Baselga J., Status of PI3K İnhibition and Biomarker Development in Cancer Therapeutics, Ann. Oncol., 21(4) (2009) 683–691.
  • [7] Porta C., Paglino C., Mosca A., Targeting PI3K/Akt/mTOR Signaling in Cancer, Front. Oncol., 4(2014) 1-11.
  • [8] Janku F., Yap T. A., Meric B. F., Targeting the PI3K Pathway in Cancer: Are We Making Headway?, Nat. Rev. Clin. Oncol., 15(5) (2018) 273–291.
  • [9] Liu T., Sun Q., Li Q., Yang H., Zhang Y., Wang R., et al., Dual PI3K/Mtor Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma, Mol. Cancer Ther., 14 (2) (2015) 429–439.
  • [10] Knight S.D., Adams N.D., Burgess J.L., Chaudhari A.M., Darcy M.G., Donatelli C.A., Luengo J.I., Newlander K.A., Parrish C.A., Ridgers L.H., Sarpong M.A., Schmidt S.J., Van Aller G.S., Carson J.D., Diamond M.A., Elkins P.A., Gardiner C.M., Garver E., Gilbert S.A., Gontarek R.R., Jackson J.R., Kershner K.L., Luo L., Raha K., Sherk C.S., Sung C.M., Sutton D., Tummino P. J., Wegrzyn R. J., Auger K.R., Dhanak D., Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin, ACS Med. Chem. Lett., 1(1) (2010) 39–43.
  • [11] Bociek R.G., Adult Burkitt’s Lymphoma, Clin. Lymphoma.,6 (2005) 11–20.
  • [12] Zayac A.S., Olszewski A. J., Burkitt Lymphoma: Bridging the Gap Between Advances in Molecular Biology and Therapy, Leuk. Lymphom., 61(8) (2020) 1784–1796.
  • [13] Short N. J., Kantarjian H.M., Ko H., Khoury J.D., Ravandi F., Thomas D.A.,Garcia M.G., Khouri M., Cortes J. E., Wierda W.G., Verstovsek S., Estrov Z., Ferrajoli A., Thompson P. A., Pierce S.A., O'Brien S.M., Jabbour E., Outcomes of Adults with Relapsed or Refractory Burkitt and High-Grade B-cell Leukemia/Lymphoma, Am. J. Hematol., 92(6) (2017) 114–117.
  • [14] Sweetenham J. W., Pearce R., Taghipour G., Biaise D., Gisselbrecht C., Goldstone A.H., Adult Burkitt’s and Burkitt-like non-Hodgkin’s lymphoma - Outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: Results from the European group for blood and marrow transplantation, J. Clin. Oncol., 14(9) (1996) 2465–2472.
  • [15] Ippolito T, Mavis C, Gu J, Hernandez-Ilizaliturri F. J, Barth M. J. Omipalisib (GSK458), a Dual an-PI3K/mTOR Inhibitor, Exhibits in Vitro and In Vivo Activity in Chemotherapy-Sensitive and -Resistant Models of Burkitt Lymphoma, Blood., 132 (2018) 2951–2951.
  • [16] Li C, Xin P, Xiao H, Zheng Y, Huang Y, Zhu X. The dual PI3K/mTOR inhibitor NVP-BEZ235 Inhibits Proliferation and Induces Apoptosis of Burkitt Lymphoma Cell, Cancer Cell Int., 15 (2015) 1–9.
  • [17] Munster P, Aggarwal R, Hong D, Schellens J.H.M., Van Der Noll R., Specht J., Witteveen P.O., Werner T.L., Dees E.C., Bergsland E., Agarwal N., Kleha S.F., Durante M., Adams L., Smith D.A., Lampkin T.A., Morris S.R., Kurzrock R., First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies., Clin. Cancer Res., 22 (2016) 1932–1939.
  • [18] Wong K., Di Cristofano F., Ranieri M., De Martino D., Di Cristofano A., PI3K/mTOR Inhibition Potentiates and Extends Palbociclib Activity in Anaplastic Thyroid Cancer, Endocr. Relat. Cancer., 26 (2018) 425–436.
  • [19] Zhu D.S, Dong J.Y, Xu Y.Y, Zhang X.T, Fu S.B, Liu W., Omipalisib Inhibits Esophageal Squamous Cell Carcinoma Growth Through Inactivation of Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) and ERK Signaling, Med. Sci. Monit., 26( 2020) e927106.
There are 19 citations in total.

Details

Primary Language English
Subjects Pharmacology and Pharmaceutical Sciences (Other)
Journal Section Natural Sciences
Authors

Zekeriya Keskin 0000-0003-3623-9892

Fatih Yulak 0000-0003-3708-6752

Hatice Terzi 0000-0003-3471-1305

Merve İnanır 0000-0003-4661-8087

Project Number T-896
Publication Date December 28, 2023
Submission Date August 16, 2023
Acceptance Date December 2, 2023
Published in Issue Year 2023Volume: 44 Issue: 4

Cite

APA Keskin, Z., Yulak, F., Terzi, H., İnanır, M. (2023). Evaluation of the Antitumor Activity of Omipalisib, a PI3K/AKT/MTOR Pathway Inhibitor, on Burkitt Lymphoma Cell Line. Cumhuriyet Science Journal, 44(4), 635-639. https://doi.org/10.17776/csj.1344535
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