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Int. J. Mol. Sci. 2018, 19(1), 277; https://doi.org/10.3390/ijms19010277

Induction of Pro-Apoptotic Endoplasmic Reticulum Stress in Multiple Myeloma Cells by NEO214, Perillyl Alcohol Conjugated to Rolipram

1
Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
3
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
Current address: University of Tennessee, Knoxville, TN 37996, USA.
*
Authors to whom correspondence should be addressed.
Received: 24 November 2017 / Revised: 24 December 2017 / Accepted: 11 January 2018 / Published: 17 January 2018
(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)
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Abstract

Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination. The cytotoxic mechanism of NEO214 involved severe ER stress and prolonged induction of CCAAT/enhancer-binding protein homologous protein (CHOP), a key pro-apoptotic component of the ER stress response. These effects were prevented by salubrinal, a pharmacologic inhibitor of ER stress, and by CHOP gene knockout. Conversely, combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. Combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 3′,5′-monophosphate (AMP) pathways might play a lesser role. Our study introduces the novel agent NEO214 as a potent inducer of ER stress with significant anti-MM activity in vitro. It should be further investigated as a potential MM therapy aimed at exploiting this tumor’s distinct sensitivity to ER stress. View Full-Text
Keywords: bortezomib; CHOP; perillyl alcohol; phosphodiesterase; rolipram bortezomib; CHOP; perillyl alcohol; phosphodiesterase; rolipram
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Chen, T.C.; Chan, N.; Labib, S.; Yu, J.; Cho, H.-Y.; Hofman, F.M.; Schönthal, A.H. Induction of Pro-Apoptotic Endoplasmic Reticulum Stress in Multiple Myeloma Cells by NEO214, Perillyl Alcohol Conjugated to Rolipram. Int. J. Mol. Sci. 2018, 19, 277.

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