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A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.

Chu B, Liu F, Li L, Ding C, Chen K, Sun Q, Shen Z, Tan Y, Tan C, Jiang Y - Cell Death Dis (2015)

Bottom Line: We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis.The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo.On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China [2] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.

ABSTRACT
Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C(16)H(14)ClN(3)O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

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5A exerted cytotoxic activity in breast cancer cells. (a) The structure of 5a. (b) Breast cancer cells were treated with increasing concentrations of 5a for 72 h, cell viability was analyzed by MTT assay. (c) Cell viability, as determined by colony formation assay, was assessed in breast cancer cells treated with 5a. (d) Cells were cultured with 5  or 10 μM 5a for 48 h and then subjected to apoptosis assay, using flow cytometry. (e) Breast cancer cells treated with 5 or 10 μM 5a for indicated time points were stained with Hoechst 33258 dye; apoptotic bodies and chromatin condensation were revealed under a fluorescence microscopy; scale bar, 20 μm
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fig1: 5A exerted cytotoxic activity in breast cancer cells. (a) The structure of 5a. (b) Breast cancer cells were treated with increasing concentrations of 5a for 72 h, cell viability was analyzed by MTT assay. (c) Cell viability, as determined by colony formation assay, was assessed in breast cancer cells treated with 5a. (d) Cells were cultured with 5  or 10 μM 5a for 48 h and then subjected to apoptosis assay, using flow cytometry. (e) Breast cancer cells treated with 5 or 10 μM 5a for indicated time points were stained with Hoechst 33258 dye; apoptotic bodies and chromatin condensation were revealed under a fluorescence microscopy; scale bar, 20 μm

Mentions: Multiple studies have demonstrated various bioactivities of benzimidazole derivatives, including anti-inflammatory,20 antioxidant,21 antiviral,22 antimicrobial23 and anticarcinogenic activity.24, 25, 26, 27, 28 Their antitumor activity may act through the inhibition of poly (ADP-ribose) polymerase-1 (PARP-1),24 topoisomerase I,25 cell cycle checkpoint kinase 226 and tyrosine kinases.27, 28 One of these analogs, 2-aryl benzimidazole compound (5a; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C16H14ClN3O, MW299) (Figure 1a), is a novel benzimidazole derivative, which was found to induce apoptosis in a human hepatocellular carcinoma cell (Hep G2),27 but the mechanism by which it induces apoptosis and antitumor activity in breast cancers is largely unknown. In this study, we demonstrate that 5a-induced cell cycle arrest and apoptosis by inhibiting EGFR and HER2 activity and downstream activation of PI3K/Akt and MEK/Erk pathways. 5A also induced apoptosis through JNK-mediated DR5 upregulation in human breast cancer cells. This study demonstrates that 5a is a novel multitarget antitumor drug candidate that has great potential as a novel agent for anticancer therapy.


A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells.

Chu B, Liu F, Li L, Ding C, Chen K, Sun Q, Shen Z, Tan Y, Tan C, Jiang Y - Cell Death Dis (2015)

5A exerted cytotoxic activity in breast cancer cells. (a) The structure of 5a. (b) Breast cancer cells were treated with increasing concentrations of 5a for 72 h, cell viability was analyzed by MTT assay. (c) Cell viability, as determined by colony formation assay, was assessed in breast cancer cells treated with 5a. (d) Cells were cultured with 5  or 10 μM 5a for 48 h and then subjected to apoptosis assay, using flow cytometry. (e) Breast cancer cells treated with 5 or 10 μM 5a for indicated time points were stained with Hoechst 33258 dye; apoptotic bodies and chromatin condensation were revealed under a fluorescence microscopy; scale bar, 20 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385914&req=5

fig1: 5A exerted cytotoxic activity in breast cancer cells. (a) The structure of 5a. (b) Breast cancer cells were treated with increasing concentrations of 5a for 72 h, cell viability was analyzed by MTT assay. (c) Cell viability, as determined by colony formation assay, was assessed in breast cancer cells treated with 5a. (d) Cells were cultured with 5  or 10 μM 5a for 48 h and then subjected to apoptosis assay, using flow cytometry. (e) Breast cancer cells treated with 5 or 10 μM 5a for indicated time points were stained with Hoechst 33258 dye; apoptotic bodies and chromatin condensation were revealed under a fluorescence microscopy; scale bar, 20 μm
Mentions: Multiple studies have demonstrated various bioactivities of benzimidazole derivatives, including anti-inflammatory,20 antioxidant,21 antiviral,22 antimicrobial23 and anticarcinogenic activity.24, 25, 26, 27, 28 Their antitumor activity may act through the inhibition of poly (ADP-ribose) polymerase-1 (PARP-1),24 topoisomerase I,25 cell cycle checkpoint kinase 226 and tyrosine kinases.27, 28 One of these analogs, 2-aryl benzimidazole compound (5a; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C16H14ClN3O, MW299) (Figure 1a), is a novel benzimidazole derivative, which was found to induce apoptosis in a human hepatocellular carcinoma cell (Hep G2),27 but the mechanism by which it induces apoptosis and antitumor activity in breast cancers is largely unknown. In this study, we demonstrate that 5a-induced cell cycle arrest and apoptosis by inhibiting EGFR and HER2 activity and downstream activation of PI3K/Akt and MEK/Erk pathways. 5A also induced apoptosis through JNK-mediated DR5 upregulation in human breast cancer cells. This study demonstrates that 5a is a novel multitarget antitumor drug candidate that has great potential as a novel agent for anticancer therapy.

Bottom Line: We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis.The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo.On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China [2] The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, People's Republic of China.

ABSTRACT
Aberrant expression or function of epidermal growth factor receptor (EGFR) or the closely related human epidermal growth factor receptor 2 (HER2) can promote cell proliferation and survival, thereby contributing to tumorigenesis. Specific antibodies and low-molecular-weight tyrosine kinase inhibitors of both proteins are currently in clinical trials for cancer treatment. Benzimidazole derivatives possess diverse biological activities, including antitumor activity. However, the anticancer mechanism of 5a (a 2-aryl benzimidazole compound; 2-chloro-N-(2-p-tolyl-1H-benzo[d]imidazol-5-yl)acetamide, C(16)H(14)ClN(3)O, MW299), a novel 2-aryl benzimidazole derivative, toward breast cancer is largely unknown. Here, we demonstrate that 5a potently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosine phosphorylation and preventing downstream activation of PI3K/Akt and MEK/Erk pathways in vitro and in vivo. We also show that 5a inhibited the phosphorylation of FOXO and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in the G1-phase cell cycle arrest and apoptosis. Moreover, 5a potently induced apoptosis via the c-Jun N-terminal kinase (JNK)-mediated death receptor 5 upregulation in breast cancer cells. The antitumor activity of 5a was consistent with additional results demonstrating that 5a significantly reduced tumor volume in nude mice in vivo. Analysis of the primary breast cancer cell lines with HER2 overexpression further confirmed that 5a significantly inhibited Akt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of our findings, further development of this 2-aryl benzimidazole derivative, a new class of multitarget anticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.

Show MeSH
Related in: MedlinePlus