Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells

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Abstract

Purpose

This work aimed to investigate the effect of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on cell cycle distribution and radiosensitivity of human hepatocellular carcinoma (HCC) cells.

Methods

The assessment used in this study included: cell viability assay, cell cycle analysis by DNA histogram, expression of phosphorylated histone H3 (Ser 10) by flow cytometer, mitotic index by Liu's stain and morphological observation, mitotic spindle alignment by immunofluorescence of alpha-tubulin, expression of cell cycle-related proteins by Western blotting, and radiation survival by clonogenic assay.

Results

Our results show that costunolide reduced the viability of HA22T/VGH cells. It caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10)-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68), phosphorylated Cdc25c (Ser 216), phosphorylated Cdk1 (Tyr 15) and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9.

Conclusions

Costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human HCC cells.

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Most cited references 22

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Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors.

Frank Fan, Chin J. Wong, R Poon … (1999)

This study aimed to evaluate the long-term results of treatment and prognostic factors in patients with intrahepatic recurrence after curative resection of hepatocellular carcinoma (HCC). Recent studies have demonstrated the usefulness of re-resection, transarterial oily chemoembolization (TOCE), or percutaneous ethanol injection therapy (PEIT) in selected patients with intrahepatic recurrent HCC. The overall results of a treatment strategy combining these modalities have not been fully evaluated, and the prognostic factors determining survival in these patients remain to be clarified. Two hundred and forty-four patients who underwent curative resection for HCC were followed for intrahepatic recurrence, which was treated aggressively with a strategy including different modalities. Survival results after recurrence and from initial hepatectomy were analyzed, and prognostic factors were determined by univariate and multivariate analysis using 27 clinicopathologic variables. One hundred and five patients (43%) with intrahepatic recurrence were treated with re-resection (11), TOCE (71), PEIT (6), systemic chemotherapy (8) or conservatively (9). The overall 1-year, 3-year, and 5-year survival rates from the time of recurrence were 65.5%, 34.9%, and 19.7%, respectively, and from the time of initial hepatectomy were 78.4%, 47.2%, and 30.9%, respectively. The re-resection group had the best survival, followed by the TOCE group. Multivariate analysis revealed Child's B or C grading, serum albumin < or = 40 g/l, multiple recurrent tumors, recurrence < or = 1 year after hepatectomy, and concurrent extrahepatic recurrence to be independent adverse prognostic factors. Aggressive treatment with a multimodality strategy could result in prolonged survival in patients with intrahepatic recurrence after curative resection for HCC. Prognosis was determined by the liver function status, interval to recurrence, number of recurrent tumors, any concurrent extrahepatic recurrence, and type of treatment.

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X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells.

W Sinclair, Kelly R Morton (1966)

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Dose-response relationship in local radiotherapy for hepatocellular carcinoma.

Chae Yoon Chon, Y Moon, C. Suh … (2002)

Dose escalation using three-dimensional conformal radiotherapy (3D-CRT) is based on the hypothesis that increasing the dose can enhance tumor control. This study aimed to determine whether a dose-response relationship exists in local radiotherapy for primary hepatocellular carcinoma (HCC). One hundred fifty-eight patients were enrolled in the present study between January 1992 and March 2000. The exclusion criteria included the presence of an extrahepatic metastasis, liver cirrhosis of Child class C, tumors occupying more than two-thirds of the entire liver, and a performance status on the Eastern Cooperative Oncology Group scale of more than 3. Radiotherapy was given to the field, including the tumor, with generous margin using 6- or 10-MV X-rays. The mean radiation dose was 48.2 +/- 7.9 Gy in daily 1.8-Gy fractions. The tumor response was assessed based on diagnostic radiologic examinations, including a computed tomography scan, magnetic resonance imaging, and hepatic artery angiography 4-8 weeks after the completion of treatment. Liver toxicity and gastrointestinal complications were evaluated. An objective response was observed in 106 of 158 (67.1%) patients. Statistical analysis revealed that the total dose was the most significant factor associated with the tumor response. The response rates in patients treated with doses 50 Gy were 29.2%, 68.6%, and 77.1%, respectively. Survivals at 1 and 2 years after radiotherapy were 41.8% and 19.9%, respectively, with a median survival time of 10 months. The rate of liver toxicity according to the doses 50 Gy was 4.2%, 5.9%, and 8.4%, respectively, and the rate of gastrointestinal complications was 4.2%, 9.9%, and 13.2%, respectively. The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response. The results of this study showed that 3D-CRT can theoretically be used for treating primary HCC.

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Author and article information

Journal

Journal ID (nlm-ta): Radiat Oncol

Title: Radiation Oncology (London, England)

Publisher: BioMed Central

ISSN (Electronic): 1748-717X

Publication date Collection: 2011

Publication date (Electronic): 30 May 2011

Volume: 6

Page: 56

Affiliations

[1 ]Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan

[2 ]Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan

[3 ]Section of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan

[4 ]Department of Radiation Oncology, Mackay Memorial Hospital, Taipei, Taiwan

[5 ]Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan

Article

Publisher ID: 1748-717X-6-56

DOI: 10.1186/1748-717X-6-56

PMC ID: 3123574

PubMed ID: 21624128

SO-VID: c682af8c-fdfd-4b04-944e-0a26057d3458

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 1 February 2011

Date accepted : 30 May 2011

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Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells

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Cancer Immunotherapy

Most cited references 22

Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors.

X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells.

Dose-response relationship in local radiotherapy for hepatocellular carcinoma.

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