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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 death in vivo and delays tumor growth in myeloma xenograft models. Human multiple myeloma cells (RPMI-8226 and OPM2) were injected subcutaneously into nude mice with a density of 30 million cells/site. When tumors were palpable, mice (n = 10/group) were orally given BENC-511 (50 mg/Kg body weight) in PBS containing 10% Tween 80 and 10% DMSO daily for continuous 20 days. Tumor volumes (A) were monitored every other day. *, p < 0.05; #, p < 0.01. Tumor samples from each group were subject to immunoblotting analysis for PARP, Caspase-3, phospho-AKT, T-AKT, p-mTOR, T-mTOR, p-p70S6K, and p70S6K with specific antibodies (B, C, and D).
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Figure 7: BENC-511 induces MM cell death in vivo and delays tumor growth in myeloma xenograft models. Human multiple myeloma cells (RPMI-8226 and OPM2) were injected subcutaneously into nude mice with a density of 30 million cells/site. When tumors were palpable, mice (n = 10/group) were orally given BENC-511 (50 mg/Kg body weight) in PBS containing 10% Tween 80 and 10% DMSO daily for continuous 20 days. Tumor volumes (A) were monitored every other day. *, p < 0.05; #, p < 0.01. Tumor samples from each group were subject to immunoblotting analysis for PARP, Caspase-3, phospho-AKT, T-AKT, p-mTOR, T-mTOR, p-p70S6K, and p70S6K with specific antibodies (B, C, and D).

Mentions: To further evaluate the therapeutic effects of BENC-511 in MM, two myeloma tumor models established with human MM cell lines OPM2 and RPMI-8226 in nude mice were treated with BENC-511 by oral administration. As shown in Figure 7A, BENC-511 at 50 mg/kg/day significantly decreased tumor growth within one week in both models. BENC-511 delayed MM tumor growth in a time-dependent manner. At the end of the experiment with 20-day treatment, the average tumor sizes were decreased to 25% and 21.2% compared with the control treated with vehicle in OPM2 and RPMI-8226 models, respectively (Figure 7A).


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 death in vivo and delays tumor growth in myeloma xenograft models. Human multiple myeloma cells (RPMI-8226 and OPM2) were injected subcutaneously into nude mice with a density of 30 million cells/site. When tumors were palpable, mice (n = 10/group) were orally given BENC-511 (50 mg/Kg body weight) in PBS containing 10% Tween 80 and 10% DMSO daily for continuous 20 days. Tumor volumes (A) were monitored every other day. *, p < 0.05; #, p < 0.01. Tumor samples from each group were subject to immunoblotting analysis for PARP, Caspase-3, phospho-AKT, T-AKT, p-mTOR, T-mTOR, p-p70S6K, and p70S6K with specific antibodies (B, C, and D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: BENC-511 induces MM cell death in vivo and delays tumor growth in myeloma xenograft models. Human multiple myeloma cells (RPMI-8226 and OPM2) were injected subcutaneously into nude mice with a density of 30 million cells/site. When tumors were palpable, mice (n = 10/group) were orally given BENC-511 (50 mg/Kg body weight) in PBS containing 10% Tween 80 and 10% DMSO daily for continuous 20 days. Tumor volumes (A) were monitored every other day. *, p < 0.05; #, p < 0.01. Tumor samples from each group were subject to immunoblotting analysis for PARP, Caspase-3, phospho-AKT, T-AKT, p-mTOR, T-mTOR, p-p70S6K, and p70S6K with specific antibodies (B, C, and D).
Mentions: To further evaluate the therapeutic effects of BENC-511 in MM, two myeloma tumor models established with human MM cell lines OPM2 and RPMI-8226 in nude mice were treated with BENC-511 by oral administration. As shown in Figure 7A, BENC-511 at 50 mg/kg/day significantly decreased tumor growth within one week in both models. BENC-511 delayed MM tumor growth in a time-dependent manner. At the end of the experiment with 20-day treatment, the average tumor sizes were decreased to 25% and 21.2% compared with the control treated with vehicle in OPM2 and RPMI-8226 models, respectively (Figure 7A).

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