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

Tara M. Nordgren, Ganapati V. Hegde, Shantaram S Joshi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)61-68
Number of pages8
JournalJournal of Cancer Science and Therapy
Volume4
Issue number4
DOIs
StatePublished - Jun 28 2012

Fingerprint

Mantle-Cell Lymphoma
Ritonavir
Therapeutics
Vincristine
Non-Hodgkin's Lymphoma
Down-Regulation
Apoptosis
Recurrence
Cell Line
B-Cell Lymphoma
Hematologic Neoplasms

Keywords

  • Mantle cell lymphoma
  • NFκB
  • Protease inhibitors
  • Refractory lymphoma
  • Ritonavir
  • Survivin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ritonavir exhibits limited efficacy as a single agent in treating aggressive mantle cell lymphoma. / Nordgren, Tara M.; Hegde, Ganapati V.; Joshi, Shantaram S.

In: Journal of Cancer Science and Therapy, Vol. 4, No. 4, 28.06.2012, p. 61-68.

Research output: Contribution to journalArticle

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abstract = "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.",
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AB - 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.

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