NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity
by
, , ,
Thomas C. Chen
1,2,*
,
Radu O. Minea
1,2
,
Steve Swenson
1,
Zhuoyue Yang
3,
Thu Zan Thein
1 and
Axel H. Schönthal
3,*
1
Department of Neurosurgery, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA 90089, USA
2
USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
3
Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(24), 6065; https://doi.org/10.3390/cancers14246065
Submission received: 16 October 2022
/
Revised: 1 December 2022
/
Accepted: 7 December 2022
/
Published: 9 December 2022
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
Simple Summary
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow, where cancer cells are unable to complete the maturation process towards white blood cells, but instead continue to proliferate. We are developing a novel chemotherapeutic drug, NEO212, that has shown anticancer activity in different preclinical cancer models, including AML. In the current study, we demonstrate that NEO212 forces AML cells to resume the differentiation process and progress towards the macrophage phenotype, which is accompanied by a loss of proliferation. NEO212 is able to achieve this growth-inhibitory effect even in AML cells that are resistant to other chemotherapeutic drugs in clinical use, such as cytarabine and temozolomide. In mouse models with AML, we found that treatment with NEO212 was well tolerated and resulted in an apparent cure of these animals. We propose that NEO212 should be developed further and evaluated in clinical trials with AML patients.
Abstract
Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.
