Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Abstract

Simple SummaryMany patients are still dying from acute myeloid leukemia (AML). Initial treatment of this blood-borne cancer consists of chemotherapy, usually with the agent cytarabine (AraC). However, the cancer cells can become drug resistant and unresponsive to AraC, which complicates further treatment and worsens prognosis. More effective treatments are needed. We are developing a novel anticancer compound called NEO212. We investigated its AML-therapeutic potential with the use of AraC-resistant AML cells grown in culture and in mice implanted with such AML cells. We found that NEO212 effectively killed AML cells in culture. The majority of AML mice that received NEO212 treatment survived and thrived without signs of tumor recurrence. At the same time, NEO212 treatment did not result in any detectable side effects, showing that this drug was very well tolerated by these animals. We deem it worthwhile to further develop NEO212 toward its evaluation in AML patients, in particular in those where initial therapy with AraC has failed.Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.