Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer

L. Li; S. L. Zhao; G.G.L. Yue; T. P. Wong; J. X. Pu; H. D. Sun; K. P. Fung; P. C. Leung; Q.B.  Han; C.B.S. Lau; P. S. Leung

doi:10.1016/j.phymed.2018.03.055

Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer

L. Li^*, S. L. Zhao, G.G.L. Yue, T. P. Wong, J. X. Pu, H. D. Sun, K. P. Fung, P. C. Leung, Q.B. Han, C.B.S. Lau, P. S. Leung^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

11 Citations (Scopus)

Abstract

Background

Pancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy.

Purpose

Our previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied.

Methods

The anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting.

Results

The combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination.

Conclusion

Gem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.

Original language	English
Pages (from-to)	56-64
Number of pages	9
Journal	Phytomedicine
Volume	44
DOIs	https://doi.org/10.1016/j.phymed.2018.03.055
Publication status	Published - 15 May 2018

Scopus Subject Areas

Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Complementary and alternative medicine

User-Defined Keywords

Eriocalyxin B
Gemcitabine
Isodon eriocalyx
Pancreatic cancer
Synergism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.phymed.2018.03.055

Cite this

@article{8bd52c396a804f969c95c1874018baf7,

title = "Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer",

abstract = "BackgroundPancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy. PurposeOur previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied.MethodsThe anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting. ResultsThe combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination. ConclusionGem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.",

keywords = "Eriocalyxin B, Gemcitabine, Isodon eriocalyx, Pancreatic cancer, Synergism",

author = "L. Li and Zhao, {S. L.} and G.G.L. Yue and Wong, {T. P.} and Pu, {J. X.} and Sun, {H. D.} and Fung, {K. P.} and Leung, {P. C.} and Q.B. Han and C.B.S. Lau and Leung, {P. S.}",

note = "Funding Information: This work was supported by the Food and Health Bureau, Hong Kong Special Administrative Region, under Health and Medical Research Fund, No. 10110021. Publisher copyright: {\textcopyright} 2018 Elsevier GmbH. All rights reserved.",

year = "2018",

month = may,

day = "15",

doi = "10.1016/j.phymed.2018.03.055",

language = "English",

volume = "44",

pages = "56--64",

journal = "Phytomedicine",

issn = "0944-7113",

publisher = "Elsevier",

}

TY - JOUR

T1 - Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer

AU - Li, L.

AU - Zhao, S. L.

AU - Yue, G.G.L.

AU - Wong, T. P.

AU - Pu, J. X.

AU - Sun, H. D.

AU - Fung, K. P.

AU - Leung, P. C.

AU - Han, Q.B.

AU - Lau, C.B.S.

AU - Leung, P. S.

N1 - Funding Information: This work was supported by the Food and Health Bureau, Hong Kong Special Administrative Region, under Health and Medical Research Fund, No. 10110021. Publisher copyright: © 2018 Elsevier GmbH. All rights reserved.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - BackgroundPancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy. PurposeOur previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied.MethodsThe anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting. ResultsThe combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination. ConclusionGem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.

AB - BackgroundPancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy. PurposeOur previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied.MethodsThe anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting. ResultsThe combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination. ConclusionGem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.

KW - Eriocalyxin B

KW - Gemcitabine

KW - Isodon eriocalyx

KW - Pancreatic cancer

KW - Synergism

UR - http://www.scopus.com/inward/record.url?scp=85047143103&partnerID=8YFLogxK

U2 - 10.1016/j.phymed.2018.03.055

DO - 10.1016/j.phymed.2018.03.055

M3 - Journal article

C2 - 29895493

AN - SCOPUS:85047143103

SN - 0944-7113

VL - 44

SP - 56

EP - 64

JO - Phytomedicine

JF - Phytomedicine

ER -

Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer

Abstract

Scopus Subject Areas

User-Defined Keywords

UN SDGs

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