6,7-dihydroxy-2-(4′-hydroxyphenyl)naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway

Ching Feng Chiu, Guan Ying Lai, Chung Hwan Chen, Chien Chao Chiu, Shao Wen Hung, Chi Fen Chang

Research output: Contribution to journalArticle

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Abstract

Background: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4′-hydroxyphenyl) naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells. Methods: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting. Results: PNAP-6 was shown to have an IC50 value 15.20 μM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s. Conclusion: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer.

Original languageEnglish
Pages (from-to)1609-1621
Number of pages13
JournalDrug Design, Development and Therapy
Volume13
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

HCT116 Cells
Endoplasmic Reticulum Stress
Colorectal Neoplasms
Apoptosis
Cyclin B
Propidium
G2 Phase
Annexin A5
Caspases
Cell Division
Inhibitory Concentration 50
Chromatin
Cell Survival
Proteins
Western Blotting
Staining and Labeling
Growth
Pharmaceutical Preparations
naphthalene
Neoplasms

Keywords

  • 2-phenylnaphthalenes
  • Colorectal cancer
  • Endoplasmic reticulum stress
  • Extrinsic apoptosis pathway

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

Cite this

6,7-dihydroxy-2-(4′-hydroxyphenyl)naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway. / Chiu, Ching Feng; Lai, Guan Ying; Chen, Chung Hwan; Chiu, Chien Chao; Hung, Shao Wen; Chang, Chi Fen.

In: Drug Design, Development and Therapy, Vol. 13, 01.01.2019, p. 1609-1621.

Research output: Contribution to journalArticle

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abstract = "Background: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4′-hydroxyphenyl) naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells. Methods: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting. Results: PNAP-6 was shown to have an IC50 value 15.20 μM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s. Conclusion: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer.",
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T1 - 6,7-dihydroxy-2-(4′-hydroxyphenyl)naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway

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AU - Chen, Chung Hwan

AU - Chiu, Chien Chao

AU - Hung, Shao Wen

AU - Chang, Chi Fen

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N2 - Background: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4′-hydroxyphenyl) naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells. Methods: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting. Results: PNAP-6 was shown to have an IC50 value 15.20 μM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s. Conclusion: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer.

AB - Background: Colorectal cancer is the third leading cause of cancer-related deaths worldwide, and therefore, the development of novel drugs for its prevention and therapy are urgently required. This study aimed to determine the molecular mechanism of 6,7-dihydroxy-2-(4′-hydroxyphenyl) naphthalene (PNAP-6)-induced cytotoxicity in human colorectal cancer (HCT116) cells. Methods: The effects of 2-phenylnaphthalene derivatives on HCT116 cell growth and viability were assessed by MTT assays. The mechanisms involved in the regulation of the extrinsic apoptosis and endoplasmic reticulum (ER) stress pathways by PNAP-6 were analyzed by annexin-V/propidium iodide flow cytometric analysis, Hoechst 33342 fluorescent staining, and Western blotting. Results: PNAP-6 was shown to have an IC50 value 15.20 μM. It induced G2/M phase arrest in HCT116 cells, associated with a marked decrease in cyclin B and CDK1 protein expression and increased caspase activation, PARP cleavage, chromatin condensation, and sub-G1 apoptosis. Moreover, we found that the apoptotic effects of PNAP-6 proceeded through extrinsic apoptosis and ER stress pathways, by increasing the expression of Fas protein and ER stress markers, including PERK, ATF4, CHOP, p-IRE1α, and XBP-1s. Conclusion: These results suggest that 2-phenylnaphthalene derivatives, such as PNAP-6, have potential as new treatments for colorectal cancer.

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KW - Colorectal cancer

KW - Endoplasmic reticulum stress

KW - Extrinsic apoptosis pathway

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