Abstract
The first-choice drug for acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA), frequently causes drug-resistance and some adverse effects. Thus, an effective and safe agent for ATRA-resistant APL is needed. Menaquinone-4 (MK-4, vitamin K2(20)), used for osteoporosis treatment, does not have serious adverse effects. It has been reported that MK-4 has growth-inhibitory effects on HL60 cells by inducing apoptosis via the activation of Bcl-2 antagonist killer 1 (BAK). However, the effect of MK-4 on ATRA-resistant APL has not been reported. Here, we show that ester derivatives of menahydroquinone-4 (MKH; a reduced form of MK-4), MKH 1,4-bis-N,N-dimethylglycinate (MKH-DMG) and MKH 1,4-bis-hemi-succinate (MKH-SUC), exerted strong growth-inhibitory effects even on ATRA-resistant HL60 (HL-60R) cells compared with ATRA and MK-4. MKH delivery after MKH-SUC treatment was higher than that after MK-4 treatment, and the results indicated apoptosis induced by BAK activation. In contrast, for MKH-DMG, reconversion to MKH was slow and apoptosis was not observed. We suggest that the ester forms, including monoesters of MKH-DMG, exhibit another mechanism independent of apoptosis. In conclusion, the MKH derivatives (MKH-SUC and MKH-DMG) inhibited not only HL60 cells but also HL-60R cells, indicating a potential to overcome ATRA resistance.
Highlights
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML)
For All-trans retinoic acid (ATRA) treatment, the viability curve of the HL-60R cells shifted towards the higher doses represented on the HL60 cell curve (Figure 2A)
For the MK-4 treatment, the curve of the HL-60R cells shifted towards the higher doses for HL60 cells (Figure 2B)
Summary
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). All-trans retinoic acid (ATRA), known as tretinoin, a molecularly targeted drug, has been used for the initial (induction) treatment of APL in combination with anthracyclines. There is a demand for effective and safe agents for ATRA-resistant APL. HL60 was initially classified as an APL cell line, and ATRA was found to induce its differentiation; this discovery led to numerous studies [6,7]. HL60 was later reclassified as a non-APL cell line [8]. Because the aim of this study was to discover drug candidates that potentially overcome ATRA resistance, we used HL60 and HL-60R (ATRA-resistant HL60) as ATRA-responsive cell lines
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