Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762

Jing Nan Wang, Yun Che, Zu Yang Yuan, Zhi Liang Lu, Yuan Li, Zhi Rong Zhang, Ning Li, Ren Da Li, Jun Wan, Han Dong Sun, Nan Sun, Pema Tenzin Puno, Jie He

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.

Original languageEnglish (US)
Pages (from-to)71-83
Number of pages13
JournalToxicology and Applied Pharmacology
Volume365
DOIs
StatePublished - Feb 15 2019

Fingerprint

Tumors
Growth
Neoplasms
Reactive Oxygen Species
Isodon
macrocalin B
3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
Esophageal Squamous Cell Carcinoma
Epithelial Cells
Apoptosis
Lead compounds
Cyclin B1
Caspase 9
Herbal Medicine
Diterpenes
G2 Phase
Acetylcysteine
Cell growth
p38 Mitogen-Activated Protein Kinases
Drug Discovery

Keywords

  • Acetyl-macrocalin B
  • Chk1/Chk2
  • Esophageal squamous cell carcinoma
  • Reactive oxygen species
  • p38 MAPK

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762. / Wang, Jing Nan; Che, Yun; Yuan, Zu Yang; Lu, Zhi Liang; Li, Yuan; Zhang, Zhi Rong; Li, Ning; Li, Ren Da; Wan, Jun; Sun, Han Dong; Sun, Nan; Puno, Pema Tenzin; He, Jie.

In: Toxicology and Applied Pharmacology, Vol. 365, 15.02.2019, p. 71-83.

Research output: Contribution to journalArticle

Wang, Jing Nan ; Che, Yun ; Yuan, Zu Yang ; Lu, Zhi Liang ; Li, Yuan ; Zhang, Zhi Rong ; Li, Ning ; Li, Ren Da ; Wan, Jun ; Sun, Han Dong ; Sun, Nan ; Puno, Pema Tenzin ; He, Jie. / Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762. In: Toxicology and Applied Pharmacology. 2019 ; Vol. 365. pp. 71-83.
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abstract = "Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.",
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AU - Zhang, Zhi Rong

AU - Li, Ning

AU - Li, Ren Da

AU - Wan, Jun

AU - Sun, Han Dong

AU - Sun, Nan

AU - Puno, Pema Tenzin

AU - He, Jie

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