Enhancing Effect on Tumour Apoptosis With the Use of Pentoxifylline in Patients With Hodgkin Lymphoma

Summary

Hodgkin's Lymphoma (HL) is a neoplasm that affects the lymph nodes and the lymphatic system. In Mexico, HL is the seventh most incident cancer and the ninth with the highest mortality. It is characterized by the presence of Reed-Sternberg (HRS) cells derived from B cells of the germinal center. They harbor mutations that activate the NF-κB pathway, favoring cell survival and their reprogramming. Currently, the available therapeutic options are chemotherapy and radiotherapy, achieving cure rates of 75% in patients in advanced stages, in which 70% of these are found at the time of diagnosis. The investigators proposed the use of pentoxifylline (PTX) as a therapeutic option to enhance the antitumor effect generated by the treatment since it can increase the efficacy of apoptosis, in vitro and in vivo, induced by doxorubicin, cisplatin, and adriamycin in human leukemic and cervical cancer cells, through inhibition of NF-κB by preventing phosphorylation of serine 32 of the inhibitor κB; it also decreases the expression of Bcl-2 and Bcl-XL, induces the releasement of cytochrome c and caspases 3, 9, and cleavage of caspase 8. The investigators evaluated the effects of PTX during the steroid window phase at induction to remission in pediatric patients with LLA of a recent diagnosis, where it was shown that the combined treatment of prednisone (PRD) with PTX achieves greater percentages of apoptosis compared to individual treatment. In addition, the effect of PTX on the expression of genes associated with apoptosis was evaluated; where it was shown that it activates the intrinsic and extrinsic pathways of apoptosis. Fortilin is a protein whose serum levels increase 2.4 times more after treatment with chemotherapy or radiotherapy in patients with malignancies, so it is considered a specific and sensitive biomarker of early apoptosis in vivo. The present protocol will evaluate the enhancing effect of PTX on tumor apoptosis in combination with chemotherapeutical agents in pediatric and AYA patients with HL. Apoptosis will be measured in vivo by quantifying serum levels of fortilin and cytochrome c in participants before and after treatment by ELISA; as well as an evaluation of the clinical response based on the results of the PET-Scan, overall and event-free survival according to the Kaplan-Meier curves, and the adverse effects associated with the use of PTX according to the common terminology criteria for adverse events and causality algorithms.

Timeline

Start

2022-07-11

Primary completion

2023-12-31

Completion

2024-07-01

Publications

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• Background Weniger MA, Kuppers R. Molecular biology of Hodgkin lymphoma. Leukemia. 2021 Apr;35(4):968-981. doi: 10.1038/s41375-021-01204-6. Epub 2021 Mar 8.
• Background Mathas S, Hartmann S, Kuppers R. Hodgkin lymphoma: Pathology and biology. Semin Hematol. 2016 Jul;53(3):139-47. doi: 10.1053/j.seminhematol.2016.05.007. Epub 2016 May 13.
• Background Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, de Celis-Carrillo R, del Toro-Arreola S, Castellanos-Esparza YC, Bravo-Cuellar A. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence. BMC Cancer. 2011 Nov 10;11:483. doi: 10.1186/1471-2407-11-483.
• Background Bravo-Cuellar A, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy A, del Toro-Arreola S, de Celis-Carrillo R, Sahagun-Flores JE, de Alba-Garcia JE, Hernandez-Flores G. Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence. Mol Cancer. 2010 May 19;9:114. doi: 10.1186/1476-4598-9-114.
• Background Lerma-Diaz JM, Hernandez-Flores G, Dominguez-Rodriguez JR, Ortiz-Lazareno PC, Gomez-Contreras P, Cervantes-Munguia R, Scott-Algara D, Aguilar-Lemarroy A, Jave-Suarez LF, Bravo-Cuellar A. 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 Mar 15;103(2):149-58. doi: 10.1016/j.imlet.2005.10.019. Epub 2005 Nov 18.
• Background Bravo-Cuellar A, Hernandez-Flores G, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, De Celis-Carrillo R, Aguilar-Lemarroy A, Gomez-Lomeli P, Ortiz-Lazareno PC. 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 Feb 28;20(1):13. doi: 10.1186/1423-0127-20-13.
• Background Gonzalez-Ramella O, Ortiz-Lazareno PC, Jimenez-Lopez X, Gallegos-Castorena S, Hernandez-Flores G, Medina-Barajas F, Meza-Arroyo J, Jave-Suarez LF, Lerma-Diaz JM, Sanchez-Zubieta F, Bravo-Cuellar A. Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia. Clin Transl Oncol. 2016 Apr;18(4):369-74. doi: 10.1007/s12094-015-1376-x. Epub 2015 Sep 2.
• Background Meza-Arroyo J, Bravo-Cuellar A, Jave-Suarez LF, Hernandez-Flores G, Ortiz-Lazareno P, Aguilar-Lemarroy A, Padilla-Corona M, Sanchez-Zubieta F, Gonzalez-Ramella O. Pentoxifylline Added to Steroid Window Treatment Phase Modified Apoptotic Gene Expression in Pediatric Patients With Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2018 Jul;40(5):360-367. doi: 10.1097/MPH.0000000000001152.
• Background Sinthujaroen P, Wanachottrakul N, Pinkaew D, Petersen JR, Phongdara A, Sheffield-Moore M, Fujise K. Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. BBA Clin. 2014 Dec 1;2:103-111. doi: 10.1016/j.bbacli.2014.10.002.
• Background Kuppers R. The biology of Hodgkin's lymphoma. Nat Rev Cancer. 2009 Jan;9(1):15-27. doi: 10.1038/nrc2542. Epub 2008 Dec 11.
• Background Weniger MA, Kuppers R. NF-kappaB deregulation in Hodgkin lymphoma. Semin Cancer Biol. 2016 Aug;39:32-9. doi: 10.1016/j.semcancer.2016.05.001. Epub 2016 May 21.
• Background Schwarzer R, Jundt F. Notch and NF-kappaB signaling pathways in the biology of classical Hodgkin lymphoma. Curr Mol Med. 2011 Apr;11(3):236-45. doi: 10.2174/156652411795243423.
• Background de Oliveira KA, Kaergel E, Heinig M, Fontaine JF, Patone G, Muro EM, Mathas S, Hummel M, Andrade-Navarro MA, Hubner N, Scheidereit C. A roadmap of constitutive NF-kappaB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses. Genome Med. 2016 Mar 17;8(1):28. doi: 10.1186/s13073-016-0280-5.
• Background Hinz M, Lemke P, Anagnostopoulos I, Hacker C, Krappmann D, Mathas S, Dorken B, Zenke M, Stein H, Scheidereit C. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med. 2002 Sep 2;196(5):605-17. doi: 10.1084/jem.20020062.
• Background 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 Dec;39(12):1330-1. doi: 10.1016/j.lpm.2010.07.013. No abstract available. French.
• Background Sirois I, Raymond MA, Brassard N, Cailhier JF, Fedjaev M, Hamelin K, Londono I, Bendayan M, Pshezhetsky AV, Hebert MJ. Caspase-3-dependent export of TCTP: a novel pathway for antiapoptotic intercellular communication. Cell Death Differ. 2011 Mar;18(3):549-62. doi: 10.1038/cdd.2010.126. Epub 2010 Oct 22.

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