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Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia

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Abstract

Purpose

Pentoxifylline (PTX) has been shown to increase chemotherapy-induced apoptosis. A clinical trial was developed to evaluate the effect of the addition of PTX to the induction steroid window phase in children with acute lymphoblastic leukemia (ALL).

Methods

Thirty-two children were enrolled on this study. Children with a new diagnosis of ALL were randomly assigned to receive prednisone (PRD) 40 mg/m2/day only during the 7-day treatment pre-phase (PRD group, 11 patients) or to receive PRD with PTX (10 mg/kg/day) (PTX group, 11 patients); the control group included children with normal bone marrow (10 patients). Bone marrow aspiration (BMA) was performed at diagnosis (day −7) in all groups, and at day 0 (end of PRD window) for patients with ALL (PRD and PTX groups). Apoptosis was evaluated by flow cytometry (FC) using Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) stains. Statistical analysis was performed using the Mann–Whitney U test.

Results

Apoptotic index at day −7 was similar in all groups. However, at day 0 post-treatment, apoptosis was significantly higher in the PTX group than in the PRD group (p < 0.001). There were no serious adverse effects associated with PTX.

Conclusions

PTX potentiates blast apoptosis induced by PRD in children with ALL during steroid window phase.

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References

  1. Perez-Saldivar ML, Fajardo-Gutierrez A, Bernaldez-Rios R, Martinez-Avalos A, Medina-Sanson A, Espinosa-Hernandez L, et al. Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology. BMC Cancer. 2011;11:355.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC, et al. Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia. 2009;24(2):371–82.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bowman WP, Larsen EL, Devidas M, Linda SB, Blach L, Carroll AJ, et al. Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children’s Oncology Group trial P9906. Pediatr Blood Cancer. 2011;57(4):569–77.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ocker M, Höpfner M. Apoptosis-Modulating Drugs for Improved Cancer Therapy. Eur Surg Res. 2012;48(3):111–20.

    Article  CAS  PubMed  Google Scholar 

  5. Mahmoud MF, El Shazly SM, Barakat W. Inhibition of TNF-alpha protects against hepatic ischemia-reperfusion injury in rats via NF-kappaB dependent pathway. Naunyn Schmiedebergs Arch Pharmacol. 2012;385(5):465–71.

    Article  CAS  PubMed  Google Scholar 

  6. Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, et al. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence. BMC Cancer. 2011;11:483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bravo-Cuellar A, Ortiz-Lazareno P, Lerma-Diaz J, Dominguez-Rodriguez J, Jave-Suarez L, Aguilar-Lemarroy A, et al. Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence. Mol Cancer. 2010;9(1):114.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hernandez-Flores G, Bravo-Cuellar A, Aguilar-Luna JC, Lerma-Diaz JM, Barba-Barajas M, Orbach-Arbouys S. In vitro induction of apoptosis in acute myelogenous and lymphoblastic leukemia cells by adriamycine is increased by pentoxifylline. Presse Med. 2010;39(12):1330–1.

    Article  PubMed  Google Scholar 

  9. Lerma-Diaz JM, Hernandez-Flores G, Dominguez-Rodriguez JR, Ortiz-Lazareno PC, Gomez-Contreras P, Cervantes-Munguia R, et al. In vivo and in vitro sensitization of leukemic cells to adriamycin-induced apoptosis by pentoxifylline. Involvement of caspase cascades and IkappaBalpha phosphorylation. Immunol Lett. 2006;103(2):149–58.

    Article  CAS  PubMed  Google Scholar 

  10. Bravo-Cuellar A, Hernandez-Flores G, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, De Celis-Carrillo R, et al. Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65. J Biomed Sci. 2013;20:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Barancik M, Bohacova V, Gibalova L, Sedlak J, Sulova Z, Breier A. Potentiation of anticancer drugs: effects of pentoxifylline on neoplastic cells. Int J Mol Sci. 2012;13(1):369–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rishi L, Gahlot S, Kathania M, Majumdar S. Pentoxifylline induces apoptosis in vitro in cutaneous T cell lymphoma (HuT-78) and enhances FasL mediated killing by upregulating Fas expression. Biochem Pharmacol. 2009;77(1):30–45.

    Article  CAS  PubMed  Google Scholar 

  13. Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ. Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol. 1999;19(7):5036–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schlossmacher G, Stevens A, White A. Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol. 2011;211(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  15. Nelson G, Wilde GJ, Spiller DG, Kennedy SM, Ray DW, Sullivan E, et al. NF-kappaB signalling is inhibited by glucocorticoid receptor and STAT6 via distinct mechanisms. J Cell Sci. 2003;116(Pt 12):2495–503.

    Article  CAS  PubMed  Google Scholar 

  16. Pui CH, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol. 2013;50(3):185–96.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Goicoechea M, Garcia de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, et al. Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol. 2012;25(6):969–75.

    Article  CAS  PubMed  Google Scholar 

  18. Nieder C, Zimmermann FB, Adam M, Molls M. The role of pentoxifylline as a modifier of radiation therapy. Cancer Treat Rev. 2005;31(6):448–55.

    Article  CAS  PubMed  Google Scholar 

  19. Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck. 2005;27(2):114–23.

    Article  PubMed  Google Scholar 

  20. Delanian S, Lefaix JL. Complete healing of severe osteoradionecrosis with treatment combining pentoxifylline, tocopherol and clodronate. Br J Radiol. 2002;75(893):467–9.

    Article  CAS  PubMed  Google Scholar 

  21. Goel PN, Gude RP. Delineating the anti-metastatic potential of pentoxifylline in combination with liposomal doxorubicin against breast cancer cells. Biomed Pharmacother. 2014;68(2):191–200.

    Article  CAS  PubMed  Google Scholar 

  22. Kamran MZ, Gude RP. Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway. Biomed Pharmacother. 2013;67(5):399–405.

    Article  CAS  PubMed  Google Scholar 

  23. Bajcetic M, Spasic S, Spasojevic I. Redox therapy in neonatal sepsis: reasons, targets, strategy, and agents. Shock. 2014;42(3):179–84.

    Article  CAS  PubMed  Google Scholar 

  24. Haque KN, Pammi M. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev. 2011(10):CD004205.

  25. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Chahin J, Mendez ML, Gallego E, et al. Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease: The PREDIAN Trial. Journal of the American Society of Nephrology : JASN. 2014.

  26. Galindo-Rodriguez G, Bustamante R, Esquivel-Nava G, Salazar-Exaire D, Vela-Ojeda J, Vadillo-Buenfil M, et al. Pentoxifylline in the treatment of refractory nephrotic syndrome secondary to lupus nephritis. J Rheumatol. 2003;30(11):2382–4.

    CAS  PubMed  Google Scholar 

  27. Ji Q, Zhang L, Jia H, Xu J. Pentoxifylline inhibits endotoxin-induced NF-kappa B activation and associated production of proinflammatory cytokines. Ann Clin Lab Sci. 2004;34(4):427–36.

    CAS  PubMed  Google Scholar 

  28. Rishi L, Gahlot S, Kathania M, Majumdar S. Pentoxifylline induces apoptosis in vitro in cutaneous T cell lymphoma (HuT-78) and enhances FasL mediated killing by upregulating Fas expression. Biochem Pharmacol. 2009;77(1):30–45.

    Article  CAS  PubMed  Google Scholar 

  29. Gahlot S, Khan MA, Rishi L, Majumdar S. Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors. Biochem Pharmacol. 2010;80(11):1650–61.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grant FIS/IMSS/PROT/PRIO/11/015 from FOFOI, and Red de Inmunología del Cáncer y Enfermedades Infecciosas-CONACYT-253053. We are grateful to Ph.D Dr. Carlos Rodriguez-Galindo for his kind reviewing of this manuscript.

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Authors and Affiliations

  1. Instituto de Investigación en Cáncer Infantil y de la Adolescencia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    O. Gonzalez-Ramella, X. Jiménez-López, S. Gallegos-Castorena, F. Medina-Barajas & F. Sánchez-Zubieta

  2. Department of Pediatric Hematology and Oncology, Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Guadalajara, Jalisco, Mexico

    O. Gonzalez-Ramella, X. Jiménez-López, S. Gallegos-Castorena, F. Medina-Barajas & F. Sánchez-Zubieta

  3. División de Inmunología, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Col. Independencia, 44340, Guadalajara, Jalisco, Mexico

    P. C. Ortiz-Lazareno, G. Hernández-Flores, J. Meza-Arroyo, L. F. Jave-Suárez, J. M. Lerma-Díaz & A. Bravo-Cuellar

  4. Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos, Jalisco, Mexico

    J. M. Lerma-Díaz & A. Bravo-Cuellar

Authors
  1. O. Gonzalez-Ramella
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  2. P. C. Ortiz-Lazareno
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  3. X. Jiménez-López
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  4. S. Gallegos-Castorena
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  5. G. Hernández-Flores
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  6. F. Medina-Barajas
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  7. J. Meza-Arroyo
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  8. L. F. Jave-Suárez
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  9. J. M. Lerma-Díaz
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  10. F. Sánchez-Zubieta
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  11. A. Bravo-Cuellar
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Corresponding author

Correspondence to A. Bravo-Cuellar.

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Gonzalez-Ramella, O., Ortiz-Lazareno, P.C., Jiménez-López, X. et al. Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia. Clin Transl Oncol 18, 369–374 (2016). https://doi.org/10.1007/s12094-015-1376-x

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  • DOI: https://doi.org/10.1007/s12094-015-1376-x

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