Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line
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 K<sub>2(20)</sub>), used for osteopor...
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| Online Access: | https://www.mdpi.com/1999-4923/13/5/758 |
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| author | Hirofumi Yamakawa Shuichi Setoguchi Shotaro Goto Daisuke Watase Kazuki Terada Nami Nagata-Akaho Erina Toki Mitsuhisa Koga Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata |
| author_facet | Hirofumi Yamakawa Shuichi Setoguchi Shotaro Goto Daisuke Watase Kazuki Terada Nami Nagata-Akaho Erina Toki Mitsuhisa Koga Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata |
| author_sort | Hirofumi Yamakawa |
| collection | DOAJ |
| description | 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 K<sub>2(20)</sub>), 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-<i>N</i>,<i>N</i>-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. |
| first_indexed | 2024-03-10T11:13:44Z |
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| id | doaj.art-f7dfada8c5ab4d1792ff24bb0e763734 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T11:13:44Z |
| publishDate | 2021-05-01 |
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| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-f7dfada8c5ab4d1792ff24bb0e7637342023-11-21T20:36:03ZengMDPI AGPharmaceutics1999-49232021-05-0113575810.3390/pharmaceutics13050758Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell LineHirofumi Yamakawa0Shuichi Setoguchi1Shotaro Goto2Daisuke Watase3Kazuki Terada4Nami Nagata-Akaho5Erina Toki6Mitsuhisa Koga7Kazuhisa Matsunaga8Yoshiharu Karube9Jiro Takata10Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, JapanThe 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 K<sub>2(20)</sub>), 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-<i>N</i>,<i>N</i>-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.https://www.mdpi.com/1999-4923/13/5/758drug deliveryHL60leukemiaprodrugresistanceretinoic acid |
| spellingShingle | Hirofumi Yamakawa Shuichi Setoguchi Shotaro Goto Daisuke Watase Kazuki Terada Nami Nagata-Akaho Erina Toki Mitsuhisa Koga Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line Pharmaceutics drug delivery HL60 leukemia prodrug resistance retinoic acid |
| title | Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line |
| title_full | Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line |
| title_fullStr | Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line |
| title_full_unstemmed | Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line |
| title_short | Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K<sub>2(20)</sub>, on All-Trans Retinoic Acid-Resistant HL60 Cell Line |
| title_sort | growth inhibitory effects of ester derivatives of menahydroquinone 4 the reduced form of vitamin k sub 2 20 sub on all trans retinoic acid resistant hl60 cell line |
| topic | drug delivery HL60 leukemia prodrug resistance retinoic acid |
| url | https://www.mdpi.com/1999-4923/13/5/758 |
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