Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach

Nagendra K. Chaturvedi, Rajkumar N. Rajule, Ashima Shukla, Prakash Radhakrishnan, Gordon L. Todd, Amarnath Natarajan, Julie Marie Vose, Shantaram S Joshi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB andmTORpathways are constitutively active in refractoryMCLleading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis inMCLcells including therapy-resistant cells compared with control cells. Furthermore, we observed downregulation of IκBa phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB-regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197-treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice compared with vehicle-treated mice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading to suppression of proliferation and increased apoptosis in malignantMCLcells including reduction in tumor burden in mice.

Original languageEnglish (US)
Pages (from-to)2006-2017
Number of pages12
JournalMolecular cancer therapeutics
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Mantle-Cell Lymphoma
Neoplasms
Tumor Burden
Therapeutics
Down-Regulation
Phosphorylation
Apoptosis
Quinoxalines
Inbred NOD Mouse
SCID Mice
Cyclin D1
B-Cell Lymphoma
Cell- and Tissue-Based Therapy
Non-Hodgkin's Lymphoma
Phosphotransferases
Kidney
Recurrence
Lung
Liver

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach. / Chaturvedi, Nagendra K.; Rajule, Rajkumar N.; Shukla, Ashima; Radhakrishnan, Prakash; Todd, Gordon L.; Natarajan, Amarnath; Vose, Julie Marie; Joshi, Shantaram S.

In: Molecular cancer therapeutics, Vol. 12, No. 10, 01.10.2013, p. 2006-2017.

Research output: Contribution to journalArticle

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abstract = "Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB andmTORpathways are constitutively active in refractoryMCLleading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis inMCLcells including therapy-resistant cells compared with control cells. Furthermore, we observed downregulation of IκBa phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB-regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197-treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice compared with vehicle-treated mice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading to suppression of proliferation and increased apoptosis in malignantMCLcells including reduction in tumor burden in mice.",
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AU - Radhakrishnan, Prakash

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N2 - Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB andmTORpathways are constitutively active in refractoryMCLleading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis inMCLcells including therapy-resistant cells compared with control cells. Furthermore, we observed downregulation of IκBa phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB-regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197-treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice compared with vehicle-treated mice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading to suppression of proliferation and increased apoptosis in malignantMCLcells including reduction in tumor burden in mice.

AB - Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB andmTORpathways are constitutively active in refractoryMCLleading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis inMCLcells including therapy-resistant cells compared with control cells. Furthermore, we observed downregulation of IκBa phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB-regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197-treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice compared with vehicle-treated mice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading to suppression of proliferation and increased apoptosis in malignantMCLcells including reduction in tumor burden in mice.

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