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Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia

Song, Michael M.a,b,*; Makena, Monish R.a,b,*; Hindle, Ashlya,b; Koneru, Balakrishnaa,b; Nguyen, Thinh H.a,c; Verlekar, Dattesh U.a,b; Cho, Hwangeuia,b; Maurer, Barry J.a,b,d,e; Kang, Min H.a,b,c,d; Reynolds, C. Patricka,b,c,d,e

doi: 10.1097/CAD.0000000000000696
PRECLINICAL REPORTS
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Objective All-trans-N-(4-hydroxyphenyl)retinamide or fenretinide (4-HPR) acts by reactive oxygen species (ROS) and dihydroceramides (DHCers). In early-phase clinical trials 4-HPR has achieved complete responses in T-cell lymphomas (TCL) and neuroblastoma (NB) and signals of activity in ovarian cancer (OV). We defined the activity of 4-HPR metabolites in N-(4-methoxyphenyl)retinamide (MPR), 4-oxo-N-(4-hydroxyphenyl)retinamide (oxoHPR), and the 4-HPR isomer 13-cis-fenretinide (cis-HPR) in NB, OV, and TCL cell lines cultured in physiological hypoxia.

Methods We compared the effect of 4-HPR, cis-HPR, oxoHPR, and MPR on cytotoxicity, ROS, and DHCers in a panel of TCL, NB, and OV cell lines cultured in bone marrow level physiological hypoxia (5% O2), utilizing a fluorescence-based cytotoxicity assay (DIMSCAN), flow cytometry, and quantitative mass spectrometry.

Results 4-HPR (10 µmol/l) achieved more than three logs of cell kill in nine of 15 cell lines. Cytotoxicity of 4-HPR and oxoHPR was comparable; in some cell lines, cis-HPR cytotoxicity was lower than 4-HPR, but additive when combined with 4-HPR. MPR was not cytotoxic. ROS and DHCers were equivalently increased by 4-HPR and oxoHPR in all cell lines (P<0.01), to a lesser extent by cis-HPR (P<0.01), and not increased in response to MPR (P>0.05). Mitochondrial membrane depolarization, caspase-3 cleavage, and apoptosis (TUNEL) were all significantly increased by 4-HPR and oxoHPR (P<0.01).

Conclusion Cytotoxic and pharmacodynamic activity was comparable with 4-HPR and oxoHPR, lower with cis-HPR, and MPR was inactive. Neither MPR or cis-HPR antagonized 4-HPR activity. These data support focusing on achieving high 4-HPR exposures for maximizing antineoplastic activity.

aCancer Center

Departments of bCell Biology and Biochemistry

cPharmacology and Neuroscience

dPediatrics

eInternal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas, USA

*Michael M. Song and Monish R. Makena contributed equally to the writing of this article.

Correspondence to C. Patrick Reynolds, MD, PhD, 3601 4th Street STOP 9445, Lubbock, TX 79430, USA Tel: +1 806 743 1558; fax: +1 806 743 2691; e-mail: patrick.reynolds@ttuhsc.edu

Received July 16, 2018

Accepted August 30, 2018

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