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Novel harmine derivatives for tumor targeted therapy.

Li S, Wang A, Gu F, Wang Z, Tian C, Qian Z, Tang L, Gu Y - Oncotarget (2015)

Bottom Line: Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine.However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity.Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.

ABSTRACT
Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.

No MeSH data available.


Related in: MedlinePlus

In vivo antitumor efficacy of 2DG-Har-01 and MET-Har-02 on S180 tumor-bearing mice and MCF-7 tumor-bearing nude miceA. tumor volume of mice-bearing S180 tumors under different treatments (2DG-Har-01, MET-Har-02, harmine and saline, n = 10/group). B. tumor picture of mice-bearing S180 tumors in different groups (2DG-Har-01, MET-Har-02, harmine and saline) on the 16th day after injection. C. body weights of mice bearing S180 tumors in different groups. D. the 16-day survival rates of mice after administration of 2DG-Har-01, MET-Har-02, harmine and saline. E. tumor volume of nude mice-bearing MCF-7 tumors under different treatments (MET-Har-02, harmine and saline, n = 10/group). F. body weights of mice bearing MCF-7 tumors in different groups. G. the 21-day survival rates of mice after administration of MET-Har-02, harmine and saline. H. the histology examination of tumor on different group.
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Figure 4: In vivo antitumor efficacy of 2DG-Har-01 and MET-Har-02 on S180 tumor-bearing mice and MCF-7 tumor-bearing nude miceA. tumor volume of mice-bearing S180 tumors under different treatments (2DG-Har-01, MET-Har-02, harmine and saline, n = 10/group). B. tumor picture of mice-bearing S180 tumors in different groups (2DG-Har-01, MET-Har-02, harmine and saline) on the 16th day after injection. C. body weights of mice bearing S180 tumors in different groups. D. the 16-day survival rates of mice after administration of 2DG-Har-01, MET-Har-02, harmine and saline. E. tumor volume of nude mice-bearing MCF-7 tumors under different treatments (MET-Har-02, harmine and saline, n = 10/group). F. body weights of mice bearing MCF-7 tumors in different groups. G. the 21-day survival rates of mice after administration of MET-Har-02, harmine and saline. H. the histology examination of tumor on different group.

Mentions: The in vivo anti-tumor efficiency of 2DG-Har-01 and MET-Har-02 were evaluated in S180 tumor-bearing mice following the procedures described in section method. As shown in Fig. 4A, the tumor growth was significantly reduced in the mice groups treated with 2DG-Har-01, MET-Har-02 and Harmine compared with saline-injection control group. Among all treatments, MET-Har-02 showed highest tumor inhibition ratio (67.86%) compared to 2DG-Har-01 (42.84%) and Harmine (30.93%) treatment. The tumors isolated from the subject mice after 16 days treatment confirmed the in vivo tumor measurements (Fig. 4B). Body weight and survive rate usually reflect the health condition of the treated mice. The body weight of mice in the control group (saline-treated) began to decrease from the 8th dayafter injection (Fig. 4C), which indicated the living quality of the mice was compromised by the tumor burden. For the 2DG-Har-01 and MET-Har-02 treated groups, the body weight gradually increased during the treatment period, implying that the systemic toxicity was minimal in these mice. A slightly decrease of body weight in the harmine group was observed at the end of the treatment period. During the in vivo studies of 16 days (Fig. 4D), no mice died with the 2DG-Har-01 treatment. For the same duration, the survival rate of MET-Har-02 group was 90% and harmine group was 80% while only 30% of animals survived with saline injection. These results support that the newly synthesized targeting reagents 2DG-Har-01 and MET-Har-02 treatment may prolong the life expectance of S180 tumor-bearing mice.


Novel harmine derivatives for tumor targeted therapy.

Li S, Wang A, Gu F, Wang Z, Tian C, Qian Z, Tang L, Gu Y - Oncotarget (2015)

In vivo antitumor efficacy of 2DG-Har-01 and MET-Har-02 on S180 tumor-bearing mice and MCF-7 tumor-bearing nude miceA. tumor volume of mice-bearing S180 tumors under different treatments (2DG-Har-01, MET-Har-02, harmine and saline, n = 10/group). B. tumor picture of mice-bearing S180 tumors in different groups (2DG-Har-01, MET-Har-02, harmine and saline) on the 16th day after injection. C. body weights of mice bearing S180 tumors in different groups. D. the 16-day survival rates of mice after administration of 2DG-Har-01, MET-Har-02, harmine and saline. E. tumor volume of nude mice-bearing MCF-7 tumors under different treatments (MET-Har-02, harmine and saline, n = 10/group). F. body weights of mice bearing MCF-7 tumors in different groups. G. the 21-day survival rates of mice after administration of MET-Har-02, harmine and saline. H. the histology examination of tumor on different group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496197&req=5

Figure 4: In vivo antitumor efficacy of 2DG-Har-01 and MET-Har-02 on S180 tumor-bearing mice and MCF-7 tumor-bearing nude miceA. tumor volume of mice-bearing S180 tumors under different treatments (2DG-Har-01, MET-Har-02, harmine and saline, n = 10/group). B. tumor picture of mice-bearing S180 tumors in different groups (2DG-Har-01, MET-Har-02, harmine and saline) on the 16th day after injection. C. body weights of mice bearing S180 tumors in different groups. D. the 16-day survival rates of mice after administration of 2DG-Har-01, MET-Har-02, harmine and saline. E. tumor volume of nude mice-bearing MCF-7 tumors under different treatments (MET-Har-02, harmine and saline, n = 10/group). F. body weights of mice bearing MCF-7 tumors in different groups. G. the 21-day survival rates of mice after administration of MET-Har-02, harmine and saline. H. the histology examination of tumor on different group.
Mentions: The in vivo anti-tumor efficiency of 2DG-Har-01 and MET-Har-02 were evaluated in S180 tumor-bearing mice following the procedures described in section method. As shown in Fig. 4A, the tumor growth was significantly reduced in the mice groups treated with 2DG-Har-01, MET-Har-02 and Harmine compared with saline-injection control group. Among all treatments, MET-Har-02 showed highest tumor inhibition ratio (67.86%) compared to 2DG-Har-01 (42.84%) and Harmine (30.93%) treatment. The tumors isolated from the subject mice after 16 days treatment confirmed the in vivo tumor measurements (Fig. 4B). Body weight and survive rate usually reflect the health condition of the treated mice. The body weight of mice in the control group (saline-treated) began to decrease from the 8th dayafter injection (Fig. 4C), which indicated the living quality of the mice was compromised by the tumor burden. For the 2DG-Har-01 and MET-Har-02 treated groups, the body weight gradually increased during the treatment period, implying that the systemic toxicity was minimal in these mice. A slightly decrease of body weight in the harmine group was observed at the end of the treatment period. During the in vivo studies of 16 days (Fig. 4D), no mice died with the 2DG-Har-01 treatment. For the same duration, the survival rate of MET-Har-02 group was 90% and harmine group was 80% while only 30% of animals survived with saline injection. These results support that the newly synthesized targeting reagents 2DG-Har-01 and MET-Har-02 treatment may prolong the life expectance of S180 tumor-bearing mice.

Bottom Line: Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine.However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity.Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.

ABSTRACT
Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.

No MeSH data available.


Related in: MedlinePlus