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Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization.

Han K, Xu X, Chen G, Zeng Y, Zhu J, Du X, Zhang Z, Cao B, Liu Z, Mao X - J Hematol Oncol (2014)

Bottom Line: BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression.Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP.Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu Province 215123, China. xinliangmao@suda.edu.cn.

ABSTRACT

Background: We previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application.

Methods: Six S14161 analogs were designed based on the structure-activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models.

Results: Among the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.

Conclusions: Because of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.

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BENC-511 induces MM cell apoptosis in the presence of IL-6 or IGF-1. (A) OPM2 cells were co-treated with IL-6, IGF-1 and BENC-511 with the increasing concentration for 24 hours. After incubation, cells were harvested and cell lysates were measured for the expression of PARP and GAPDH by Western blotting. (B) MM cell lines OPM2 was co-cultured overnight with human bone marrow stromal cell HS-5, followed by treatment with BENC-511 overnight. Cells were then collected for PARP, p-AKT (S473) and total AKT (T-AKT) analysis.
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Figure 6: BENC-511 induces MM cell apoptosis in the presence of IL-6 or IGF-1. (A) OPM2 cells were co-treated with IL-6, IGF-1 and BENC-511 with the increasing concentration for 24 hours. After incubation, cells were harvested and cell lysates were measured for the expression of PARP and GAPDH by Western blotting. (B) MM cell lines OPM2 was co-cultured overnight with human bone marrow stromal cell HS-5, followed by treatment with BENC-511 overnight. Cells were then collected for PARP, p-AKT (S473) and total AKT (T-AKT) analysis.

Mentions: As stated earlier, cytokines such as IL-6 and growth factors such as IGF-1 are key triggers of the PI3K/AKT signaling pathway, and critical regulators in MM cell proliferation. To find out whether BENC-511 inhibits PI3K activity is associated with its anti-myeloma activity, OPM2 cells were treated with BENC-511 from 0.5 to 4 μM or S14161 (4 μM) in the presence of IL-6 or IGF-1 for 24 hours. Apoptotic analyses with PARP suggested that BENC-511 markedly induced PARP cleavage at 1 μM, however, S14161 generated minimal effects at 4 μM. In the presence of IL-6 or IGF-1, cell death was partly blocked, especially at lower concentrations (Figure 6A). This finding demonstrated that BENC-511 induced MM cell apoptosis by targeting the PI3K signaling pathway.


Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization.

Han K, Xu X, Chen G, Zeng Y, Zhu J, Du X, Zhang Z, Cao B, Liu Z, Mao X - J Hematol Oncol (2014)

BENC-511 induces MM cell apoptosis in the presence of IL-6 or IGF-1. (A) OPM2 cells were co-treated with IL-6, IGF-1 and BENC-511 with the increasing concentration for 24 hours. After incubation, cells were harvested and cell lysates were measured for the expression of PARP and GAPDH by Western blotting. (B) MM cell lines OPM2 was co-cultured overnight with human bone marrow stromal cell HS-5, followed by treatment with BENC-511 overnight. Cells were then collected for PARP, p-AKT (S473) and total AKT (T-AKT) analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3924225&req=5

Figure 6: BENC-511 induces MM cell apoptosis in the presence of IL-6 or IGF-1. (A) OPM2 cells were co-treated with IL-6, IGF-1 and BENC-511 with the increasing concentration for 24 hours. After incubation, cells were harvested and cell lysates were measured for the expression of PARP and GAPDH by Western blotting. (B) MM cell lines OPM2 was co-cultured overnight with human bone marrow stromal cell HS-5, followed by treatment with BENC-511 overnight. Cells were then collected for PARP, p-AKT (S473) and total AKT (T-AKT) analysis.
Mentions: As stated earlier, cytokines such as IL-6 and growth factors such as IGF-1 are key triggers of the PI3K/AKT signaling pathway, and critical regulators in MM cell proliferation. To find out whether BENC-511 inhibits PI3K activity is associated with its anti-myeloma activity, OPM2 cells were treated with BENC-511 from 0.5 to 4 μM or S14161 (4 μM) in the presence of IL-6 or IGF-1 for 24 hours. Apoptotic analyses with PARP suggested that BENC-511 markedly induced PARP cleavage at 1 μM, however, S14161 generated minimal effects at 4 μM. In the presence of IL-6 or IGF-1, cell death was partly blocked, especially at lower concentrations (Figure 6A). This finding demonstrated that BENC-511 induced MM cell apoptosis by targeting the PI3K signaling pathway.

Bottom Line: BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression.Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP.Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu Province 215123, China. xinliangmao@suda.edu.cn.

ABSTRACT

Background: We previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application.

Methods: Six S14161 analogs were designed based on the structure-activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models.

Results: Among the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.

Conclusions: Because of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.

Show MeSH
Related in: MedlinePlus