MDPI - Publisher of Open Access Journals

16 pages, 4675 KB

Open AccessArticle

Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K₂₍₂₀₎, on All-Trans Retinoic Acid-Resistant HL60 Cell Line

by Hirofumi Yamakawa, Shuichi Setoguchi, Shotaro Goto, Daisuke Watase, Kazuki Terada, Nami Nagata-Akaho, Erina Toki, Mitsuhisa Koga, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Pharmaceutics 2021, 13(5), 758; https://doi.org/10.3390/pharmaceutics13050758 - 20 May 2021

Cited by 5 | Viewed by 3752

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. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

► Show Figures

Figure 1

13 pages, 2823 KB

Open AccessArticle

Prodrugs for Skin Delivery of Menahydroquinone-4, an Active Form of Vitamin K₂₍₂₀₎, Could Overcome the Photoinstability and Phototoxicity of Vitamin K₂₍₂₀₎

by Shotaro Goto, Shuichi Setoguchi, Hirofumi Yamakawa, Daisuke Watase, Kazuki Terada, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Int. J. Mol. Sci. 2019, 20(10), 2548; https://doi.org/10.3390/ijms20102548 - 24 May 2019

Cited by 13 | Viewed by 4599

Abstract

The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to the photoinstability and phototoxicity of MK-4. This study aimed to evaluate the potential of ester prodrugs of MKH for its delivery into the skin to avoid the abovementioned issues. The ester prodrugs, MKH 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG) and MKH 1,4-bis-hemisuccinate (MKH-SUC), were prepared using our previously reported methods. Photostability was determined under artificial sunlight and multi-wavelength light irradiation, phototoxicity was determined by intracellular ROS formation and cell viability of UVA-irradiated human epidermal keratinocyte cells (HaCaT), and delivery of MKH into HaCaT cells was assessed by measuring menaquinone-4 epoxide (MKO) levels. MKH prodrugs showed higher photostability than MK-4. Although MK-4 induced cellular ROS and reduced cell viability after UVA irradiation, MKH prodrugs did not affect either ROS generation or cell viability. MKH prodrugs enhanced intracellular MKO, indicating effective delivery of MKH and subsequent carboxylation activity. In conclusion, these MKH prodrugs show potential for the delivery of MKH into the skin without photoinstability and phototoxicity. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

► Show Figures

Figure 1

16 pages, 4006 KB

Open AccessArticle

Antitumor Effects and Delivery Profiles of Menahydroquinone-4 Prodrugs with Ionic or Nonionic Promoiety to Hepatocellular Carcinoma Cells

by Shuichi Setoguchi, Daisuke Watase, Kazuhisa Matsunaga, Hirofumi Yamakawa, Shotaro Goto, Kazuki Terada, Kenji Ohe, Munechika Enjoji, Yoshiharu Karube and Jiro Takata

Molecules 2018, 23(7), 1738; https://doi.org/10.3390/molecules23071738 - 16 Jul 2018

Cited by 8 | Viewed by 4370

Abstract

Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K₂) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent. Full article

(This article belongs to the Special Issue Targeted Prodrugs)

► Show Figures

Figure 1

9 pages, 671 KB

Open AccessReview

Menahydroquinone-4 Prodrug: A Promising Candidate Anti-Hepatocellular Carcinoma Agent

by Munechika Enjoji, Daisuke Watase, Kazuhisa Matsunaga, Mariko Kusuda, Nami Nagata-Akaho, Yoshiharu Karube and Jiro Takata

Diseases 2015, 3(3), 150-158; https://doi.org/10.3390/diseases3030150 - 22 Jul 2015

Cited by 2 | Viewed by 6018

Abstract

Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo. The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article. Full article

(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)

► Show Figures

Figure 1

Search Results (4)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Saved Queries

Search Filter Reset All

Years

Feature Papers

Subjects

Journals

Article Types

Countries / Regions

Search Results (4)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI