Treatment with low-dose sorafenib in combination with a novel benzimidazole derivative bearing a pyrolidine side chain provides synergistic anti-proliferative effects against human liver cancer

Ming Hua Hsu, Shih Ming Hsu, Yu Cheng Kuo, Chih Yu Liu, Cheng Ying Hsieh, Yuh Ching Twu, Chung Kwe Wang, Yuan Hsi Wang, Yi Jen Liao

Research output: Contribution to journalArticle

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Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and deadliest cancers in the world. Currently, sorafenib is the only drug that has been approved by the U.S. FDA for patients with advanced HCC. However, its improvement on patient outcomes is modest, and the median survival time is only prolonged 2-3 months. In addition, the application of sorafenib is limited because of its high cost and severe adverse side-effects. Therefore, developing more effective novel agents and reducing the dosage of sorafenib are urgently needed for HCC therapy. Here, a novel benzimidazole derivative (4a) bearing a pyrolidine side chain (9a) was synthesized. The treatments of compounds 4a, 9a and sorafenib either alone or in combination on the inhibition of liver cancer cells proliferation were measured using alamarBlue cell viability and trypan blue staining assay. Intracellular signaling pathway activities were assessed by Western blot, Q-PCR and IHC staining. The HuH7 xenograft model was used to examine antitumor activity in vivo. Adverse effects (e.g., changes in body weight, serum parameters, liver function and pathology) of mice treated with 9a were also evaluated. Compound 9a significantly inhibited HCC cell proliferation compared with 4a. In addition, 9a strongly synergized with a low dose of sorafenib in suppressing HCC cell proliferation. Regarding the activities of the signaling pathways, sorafenib did not suppress AKT signaling; however, 9a inhibited AKT and its downstream phosphorylation of p70S6K. In addition, treatment with either 9a alone or in combination with sorafenib led to the inhibition of JNK phosphorylation. However, there were no effects on the inhibition of apoptosis. The in vivo HuH7 xenograft model showed that the administration of 9a plus a low dose of sorafenib significantly decreased expression of the HCC markers α-fetoprotein, glypican-3 and survivin as well as suppressed tumor growth. Finally, there were no adverse effects in mice treated with 9a. In conclusion, co-treatment with a novel benzimidazole derivative bearing a pyrolidine side chain in combination with a low dose of sorafenib exerted significant antitumor activity in preclinical HCC models, which potentially suggests its use as a novel therapeutic strategy for patients with HCC.

Original languageEnglish
Pages (from-to)16253-16263
Number of pages11
JournalRSC Advances
Volume7
Issue number26
DOIs
Publication statusPublished - 2017

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Bearings (structural)
Cell proliferation
Liver
Phosphorylation
Derivatives
Pathology
Cell death
Tumors
Assays
Cells
Heterografts
Glypicans
Fetal Proteins
70-kDa Ribosomal Protein S6 Kinases
benzimidazole
sorafenib
Costs
Trypan Blue
Reducing Agents

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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Treatment with low-dose sorafenib in combination with a novel benzimidazole derivative bearing a pyrolidine side chain provides synergistic anti-proliferative effects against human liver cancer. / Hsu, Ming Hua; Hsu, Shih Ming; Kuo, Yu Cheng; Liu, Chih Yu; Hsieh, Cheng Ying; Twu, Yuh Ching; Wang, Chung Kwe; Wang, Yuan Hsi; Liao, Yi Jen.

In: RSC Advances, Vol. 7, No. 26, 2017, p. 16253-16263.

Research output: Contribution to journalArticle

Hsu, Ming Hua ; Hsu, Shih Ming ; Kuo, Yu Cheng ; Liu, Chih Yu ; Hsieh, Cheng Ying ; Twu, Yuh Ching ; Wang, Chung Kwe ; Wang, Yuan Hsi ; Liao, Yi Jen. / Treatment with low-dose sorafenib in combination with a novel benzimidazole derivative bearing a pyrolidine side chain provides synergistic anti-proliferative effects against human liver cancer. In: RSC Advances. 2017 ; Vol. 7, No. 26. pp. 16253-16263.
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abstract = "Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and deadliest cancers in the world. Currently, sorafenib is the only drug that has been approved by the U.S. FDA for patients with advanced HCC. However, its improvement on patient outcomes is modest, and the median survival time is only prolonged 2-3 months. In addition, the application of sorafenib is limited because of its high cost and severe adverse side-effects. Therefore, developing more effective novel agents and reducing the dosage of sorafenib are urgently needed for HCC therapy. Here, a novel benzimidazole derivative (4a) bearing a pyrolidine side chain (9a) was synthesized. The treatments of compounds 4a, 9a and sorafenib either alone or in combination on the inhibition of liver cancer cells proliferation were measured using alamarBlue cell viability and trypan blue staining assay. Intracellular signaling pathway activities were assessed by Western blot, Q-PCR and IHC staining. The HuH7 xenograft model was used to examine antitumor activity in vivo. Adverse effects (e.g., changes in body weight, serum parameters, liver function and pathology) of mice treated with 9a were also evaluated. Compound 9a significantly inhibited HCC cell proliferation compared with 4a. In addition, 9a strongly synergized with a low dose of sorafenib in suppressing HCC cell proliferation. Regarding the activities of the signaling pathways, sorafenib did not suppress AKT signaling; however, 9a inhibited AKT and its downstream phosphorylation of p70S6K. In addition, treatment with either 9a alone or in combination with sorafenib led to the inhibition of JNK phosphorylation. However, there were no effects on the inhibition of apoptosis. The in vivo HuH7 xenograft model showed that the administration of 9a plus a low dose of sorafenib significantly decreased expression of the HCC markers α-fetoprotein, glypican-3 and survivin as well as suppressed tumor growth. Finally, there were no adverse effects in mice treated with 9a. In conclusion, co-treatment with a novel benzimidazole derivative bearing a pyrolidine side chain in combination with a low dose of sorafenib exerted significant antitumor activity in preclinical HCC models, which potentially suggests its use as a novel therapeutic strategy for patients with HCC.",
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AU - Kuo, Yu Cheng

AU - Liu, Chih Yu

AU - Hsieh, Cheng Ying

AU - Twu, Yuh Ching

AU - Wang, Chung Kwe

AU - Wang, Yuan Hsi

AU - Liao, Yi Jen

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