Ritonavir exhibits limited efficacy as a single agent in treating aggressive mantle cell lymphoma

Background: Mantle Cell Lymphoma (MCL) is an aggressive B cell malignancy accounting for 6% of non- Hodgkin's lymphoma cases in the US. While various therapies are available to treat MCL, patients relapse within 3 to 4 years following treatment from therapy-resistant MCL, making MCL carry one of the worst prognoses of all non- Hodgkin's B cell lymphomas. A better understanding of the biological mechanisms of relapse and therapy-resistance in MCL is vital for developing mechanisms to target relapsing MCL, and providing better care for patients. Recent studies implicate the NFκB pathway and survivin in promotion of aggressive, therapy-resistant MCL. Therefore, we tested the efficacy of inhibiting this pathway in three MCL lines (GP, recently-developed GRL, and JVM2) using the protease inhibitor ritonavir (Abbott Laboratories), which has been shown to downregulate NFκB targets, including survivin, in other hematological malignancies. Methods: MCL cells were incubated with ritonavir then assessed for changes in proliferation, apoptosis, and activation of NFκB transcriptional targets. In addition, in vivo studies were performed to assess ritonavir's utility as a single agent in MCL treatment using an immune-deficient mouse model of human MCL. Results: When MCL cell lines were incubated with ritonavir in vitro, they exhibited reduced proliferation, increased apoptosis, and downregulation of NFκB pathway targets. However, no effect was seen when testing ritonavir as a single agent in vivo. Although, treatment with ritonavir plus vincristine in vitro revealed significant reduction in the proliferation of MCL compared to either treatment alone. Conclusions: These studies suggest ritonavir is not suitable as a single-agent therapy for MCL. However, studies combining ritonavir plus vincristine in vitro suggest ritonavir may be effective in multi-pronged treatment approaches for MCL. These findings necessitate further studies to determine ritonavir's utility within a multi-pronged treatment approach for treating therapy-resistant MCL.

[1]  D. Weisenburger,et al.  Novel therapy for therapy‐resistant mantle cell lymphoma: Multipronged approach with targeting of hedgehog signaling , 2012, International journal of cancer.

[2]  S. Carroll,et al.  Combination antiretroviral therapy as treatment for human immunodeficiency virus‐associated mucosa‐associated lymphoid tissue type lymphoma of the nasopharynx , 2011, Internal medicine journal.

[3]  A. Srirangam,et al.  The Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Lung Cancer Cells, in Part, by Inhibition of Survivin , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[4]  P. Iversen,et al.  Antisense Inhibition of Survivin Expression as a Cancer Therapeutic , 2011, Molecular Cancer Therapeutics.

[5]  C. Geisler Front-line treatment of mantle cell lymphoma , 2010, Haematologica.

[6]  I. Pastan,et al.  Immunotoxin BL22 induces apoptosis in mantle cell lymphoma (MCL) cells dependent on Bcl‐2 expression , 2010, British journal of haematology.

[7]  Yasodha Natkunam,et al.  Characterization of D-Cyclin Proteins in Hematolymphoid Neoplasms: Lack of Specificity of Cyclins D2 and D3 Expression in Lymphoma Subtypes , 2009, Modern Pathology.

[8]  W. Klapper,et al.  Differential diagnosis of cyclin D2+ mantle cell lymphoma based on fluorescence in situ hybridization and quantitative real-time-PCR , 2009, Haematologica.

[9]  B. Kahl Frontline therapy in mantle cell lymphoma: The role of high-dose therapy and integration of new agents , 2009, Current hematologic malignancy reports.

[10]  M. Leandro,et al.  Rituximab in non‐haematological disorders of adults and its mode of action , 2009, British journal of haematology.

[11]  J. Schellens,et al.  Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors , 2009, Clinical Cancer Research.

[12]  Kenji Sugimoto,et al.  Carrier-Mediated Uptake of 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide (YM155 Monobromide), a Novel Small-Molecule Survivin Suppressant, into Human Solid Tumor and Lymphoma Cells , 2009, Drug Metabolism and Disposition.

[13]  N. Mori,et al.  An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells , 2009, International journal of cancer.

[14]  W. Hiddemann,et al.  Current treatment standards and emerging strategies in mantle cell lymphoma. , 2009, Hematology. American Society of Hematology. Education Program.

[15]  A. Rosenwald,et al.  Signal transduction pathways of mantle cell lymphoma: A phosphoproteome‐based study , 2008, Proteomics.

[16]  P. Dennis,et al.  Repositioning HIV protease inhibitors as cancer therapeutics , 2008, Current opinion in HIV and AIDS.

[17]  M. Westergaard,et al.  SPC3042: a proapoptotic survivin inhibitor , 2008, Molecular Cancer Therapeutics.

[18]  M. Raffeld,et al.  Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2 , 2008, Leukemia.

[19]  H. Ovaa,et al.  Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis , 2008, Molecular Cancer Therapeutics.

[20]  T. Greiner,et al.  Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma , 2008, Molecular Cancer Therapeutics.

[21]  C. Doglioni,et al.  Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. , 2008, Blood.

[22]  Benjamin Frey,et al.  Survivin antisense oligonucleotides effectively radiosensitize colorectal cancer cells in both tissue culture and murine xenograft models. , 2008, International journal of radiation oncology, biology, physics.

[23]  Michael L. Wang,et al.  Immunotherapy in mantle cell lymphoma: Anti‐CD20‐based therapy and beyond , 2008, American journal of hematology.

[24]  E. Campo,et al.  Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics , 2007, Nature Reviews Cancer.

[25]  J. LoPiccolo,et al.  Targeting Akt in cancer therapy. , 2007, Anti-cancer drugs.

[26]  D. Weisenburger,et al.  A chromosomal translocation in cyclin D1-negative/cyclin D2-positive mantle cell lymphoma fuses the CCND2 gene to the IGK locus. , 2006, Blood.

[27]  D. Iliopoulos,et al.  Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential , 2006, Oncogene.

[28]  Christie M. Orschell,et al.  Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer , 2006, Clinical Cancer Research.

[29]  F. Cavalli,et al.  Update on the molecular biology of mantle cell lymphoma , 2006, Hematological oncology.

[30]  Mamoru Ito,et al.  leukemia cells by an HIV protease inhibitor, ritonavir , 2005 .

[31]  Nerea Martínez,et al.  Expression of the NF‐κB targets BCL2 and BIRC5/Survivin characterizes small B‐cell and aggressive B‐cell lymphomas, respectively , 2005, The Journal of pathology.

[32]  Y. Ohtsuki,et al.  HIV-1 Protease Inhibitor, Ritonavir , 2004, Cancer Research.

[33]  S. Ansell,et al.  Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma , 2004, Leukemia.

[34]  F. Bosch,et al.  Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival. , 2004, The American journal of pathology.

[35]  R. Zeldin,et al.  Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. , 2003, The Journal of antimicrobial chemotherapy.

[36]  C. Galanos,et al.  Antitumor effect of the human immunodeficiency virus protease inhibitor ritonavir: induction of tumor-cell apoptosis associated with perturbation of proteasomal proteolysis. , 2002, Cancer research.

[37]  Jie Chen,et al.  Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling , 2001, Science.

[38]  H. J. Kim,et al.  An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. , 2001, Biochemistry.

[39]  Hui Zhang,et al.  Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. , 2000, Proceedings of the National Academy of Sciences of the United States of America.