Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia

K. Chitta, Aneel Paulus, Thomas Caulfield, S. Akhtar, M. K K Blake, Sikander Ailawadhi, J. Knight, M. G. Heckman, A. Pinkerton, Asher A Chanan Khan

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Abstract

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target-ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2<sup>Ser70-Ala</sup>) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.

Original languageEnglish (US)
Article numbere260
JournalBlood Cancer Journal
Volume4
Issue number11
DOIs
StatePublished - Jan 1 2014

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Waldenstrom Macroglobulinemia
Apoptosis
Limonins
Neoplasms
Computer Simulation
Proto-Oncogene Proteins c-bcl-2
B-Lymphocytes
nimbolide
Immunoglobulin M
Immunohistochemistry
Ligands

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia. / Chitta, K.; Paulus, Aneel; Caulfield, Thomas; Akhtar, S.; Blake, M. K K; Ailawadhi, Sikander; Knight, J.; Heckman, M. G.; Pinkerton, A.; Chanan Khan, Asher A.

In: Blood Cancer Journal, Vol. 4, No. 11, e260, 01.01.2014.

Research output: Contribution to journalArticle

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abstract = "Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenstr{\"o}ms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target-ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2Ser70-Ala) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.",
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AU - Blake, M. K K

AU - Ailawadhi, Sikander

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