Lack of cross‐resistance to FF‐10501, an inhibitor of inosine‐5′‐monophosphate dehydrogenase, in azacitidine‐resistant cell lines selected from SKM‐1 and MOLM‐13 leukemia cell lines

Abstract

Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine‐resistant cells derived from SKM‐1 and MOLM‐13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth‐inhibitory effect of azacitidine, expression levels of uridine–cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross‐resistance of greater than 10‐fold (shift in IC50 value) was observed in azacitidine‐resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine‐5′‐monophosphate dehydrogenase (IMPDH) inhibitors FF‐10501 and mycophenolate mofetil (cross‐resistance to 5‐fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth‐inhibitory activities in the azacitidine‐resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF‐10501 to its active form, FF‐10501 ribosylmonophosphate [FF‐10501RMP]), FF‐10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF‐10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine.

The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes

“…34 It has been reported that SKM-1 cells had a higher IC50 of Ara-C than other myeloid leukemia cell lines, indicating that SKM-1 cells were more Ara-C resistant. 35,36 The incidences of MLL-PTD and RUNX1 mutations showed an increase in higher-risk MDS compared to lower-risk MDS. 37 Thus, SKM-1 cells and MDS mouse model cell line RUNX1 mutant-transduced Mll PTD/WT BM cells (Mll PTD/WT /RUNX1-S291fs) were used in our study.…”

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

“…SM-108 was synthesized through chemical modification of the nucleoside mizoribine [146] and was found to be effective against several hematological malignancies in Phase I and II clinical trials conducted in Japan in the late 1980s [147,148,149,150]. FF-10501 is converted to its active form, FF-10501 ribosylmonophosphate (FF-10501RMP), intracellularly by using adenine phosphoribosyl transferase [151]. It reduces cell proliferation in a dose-dependent manner by inhibiting the production of guanine nucleotides (Figure 8).…”

“…Pre-clinical studies showed the anti-leukemic effect of FF-10501 in multiple AML cell lines—MOLM13, SKM1, HL-60, U937, HEL, and OCI-AML3, including those that are resistant to hypomethylating agents [145,151]. The safety and efficacy of FF-10501 were tested in a phase I clinical trial, which is summarized in Table 5 [152,153].…”

Simultaneous and absolute quantification of nucleoside triphosphates using liquid chromatography–triple quadrupole tandem mass spectrometry

“…Moreover, nucleotide biosynthesis is an attractive target of drug discovery in the field of pharmacology. Metabolic antagonists, represented by 5-fluorouracil and hydroxyurea, inhibit nucleotide biosynthesis to kill cancer cells; thus, these types of drugs are continuously being developed [ 9 ]. Furthermore, various types of nucleoside and nucleotide analogues (including 5-fluorouracil), which have been developed as anti-cancer and anti-virus drugs [ 10 ], can induce an imbalance of cellular nucleoside triphosphates as the main effect or side effects.…”