Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. NeOnc Technologies Holdings, Inc. 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. The study 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, a combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. A combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 30,50-monophosphate (AMP) pathways might play a lesser role.
The present study shows that NEO214 can be applied to synergistically further aggravate the bortezomib-primed system toward optimized tumor cell killing. Should these in vitro synergistic outcomes be validated in the clinic, they would support the use of overall lower drug dosages, which in the patient might result in fewer side effects and overall higher quality of life during cycles of treatment. While NEO214 has not yet been tested in the clinic, this present in vitro study does provide support for the above model and encouragement for its further investigation toward clinical development.
Read The Paper
Induction of Pro-Apoptotic Endoplasmic Reticulum Stress in Multiple Myeloma Cells by NEO214, Perillyl Alcohol Conjugated to Rolipram.
Authors: Thomas C. Chen 1,*, Nymph Chan 1, Shirin Labib 2, Jiali Yu 1,†, Hee-Yeon Cho 1, Florence M. Hofman 3 and Axel H. Schönthal 2,*
2Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
3Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
* Correspondence: tcchen@usc.edu (T.C.C.); schontha@usc.edu (A.H.S.); Tel.: +1-323-442-3918 (T.C.C.); +1-323-442-1730 (A.H.S.)
† Current address: University of Tennessee, Knoxville, TN 37996, USA.
