Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53- and p21-dependent mechanism
(2012) In Oncology research 20(2-3). p.81-91- Abstract
We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53-/-, and HCT-116 p21-/- sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/Bcl-xL ratio, cleaved PARP, apoptotic nuclei... (More)
We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53-/-, and HCT-116 p21-/- sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/Bcl-xL ratio, cleaved PARP, apoptotic nuclei visualized by DAPI staining, and COMET formation. In addition, markers of autophagy were measured. Acridine orange staining revealed increased accumulation of autophagic vacuoles (AVs) after QC treatment in a dose-dependent manner in parental cells, and decreased staining in isogenic HCT-116 p53-/- and HCT-116 p21-/- cells. Immunofluorescence of LC3B was significantly lowered in QC-treated cells lacking p53 or p21, compared to the parental cells. Interestingly, the expression of the autophagy marker LC3B-II after exposure to QC was decreased in either p53 or p21 null cells compared to parental cells. After deletion of p21 in HCT-116 p53-/- cells, no change in LC3B-II expression was noted following QC treatment. Collectively, the results suggest that QC-mediated autophagy and apoptosis dependent on p53 and p21.
(Less)
- author
- Mohapatra, Purusottam LU ; Preet, Ranjan ; Das, Dipon ; Satapathy, Shakti Ranjan LU ; Choudhuri, Tathagata ; Wyatt, Michael D and Kundu, Chanakya Nath
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- keywords
- Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Autophagy/drug effects, Blotting, Western, Cell Proliferation/drug effects, Colonic Neoplasms/drug therapy, Cyclin-Dependent Kinase Inhibitor p21/metabolism, Humans, Quinacrine/pharmacology, Tumor Cells, Cultured, Tumor Suppressor Protein p53/metabolism
- in
- Oncology research
- volume
- 20
- issue
- 2-3
- pages
- 81 - 91
- publisher
- Tech Science Press
- external identifiers
-
- pmid:23193914
- scopus:84869068486
- ISSN
- 0965-0407
- DOI
- 10.3727/096504012x13473664562628
- language
- English
- LU publication?
- no
- id
- d72b8db9-866c-4149-a3d8-bddce125811d
- date added to LUP
- 2025-01-30 10:30:56
- date last changed
- 2025-06-06 13:53:22
@article{d72b8db9-866c-4149-a3d8-bddce125811d,
abstract = {{<p>We previously showed that quinacrine (QC), a small molecule antimalarial agent, also presented anticancer activity in breast cancer cells through activation of p53, p21, and inhibition of topoisomerase activity. Here we have systematically studied the detailed cell death mechanism of this drug using three colon cancer cell lines (HCT-116 parental, isogenic HCT-116 p53-/-, and HCT-116 p21-/- sublines). QC caused a dose-dependent reduction in cell viability in all three cell lines. However, the parental cells were more susceptible to QC-mediated cell death, suggesting that p53- and p21-dependent processes were involved. QC-mediated cell death was measured with the following endpoints: the Bax/Bcl-xL ratio, cleaved PARP, apoptotic nuclei visualized by DAPI staining, and COMET formation. In addition, markers of autophagy were measured. Acridine orange staining revealed increased accumulation of autophagic vacuoles (AVs) after QC treatment in a dose-dependent manner in parental cells, and decreased staining in isogenic HCT-116 p53-/- and HCT-116 p21-/- cells. Immunofluorescence of LC3B was significantly lowered in QC-treated cells lacking p53 or p21, compared to the parental cells. Interestingly, the expression of the autophagy marker LC3B-II after exposure to QC was decreased in either p53 or p21 null cells compared to parental cells. After deletion of p21 in HCT-116 p53-/- cells, no change in LC3B-II expression was noted following QC treatment. Collectively, the results suggest that QC-mediated autophagy and apoptosis dependent on p53 and p21.</p>}},
author = {{Mohapatra, Purusottam and Preet, Ranjan and Das, Dipon and Satapathy, Shakti Ranjan and Choudhuri, Tathagata and Wyatt, Michael D and Kundu, Chanakya Nath}},
issn = {{0965-0407}},
keywords = {{Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Autophagy/drug effects; Blotting, Western; Cell Proliferation/drug effects; Colonic Neoplasms/drug therapy; Cyclin-Dependent Kinase Inhibitor p21/metabolism; Humans; Quinacrine/pharmacology; Tumor Cells, Cultured; Tumor Suppressor Protein p53/metabolism}},
language = {{eng}},
number = {{2-3}},
pages = {{81--91}},
publisher = {{Tech Science Press}},
series = {{Oncology research}},
title = {{Quinacrine-mediated autophagy and apoptosis in colon cancer cells is through a p53- and p21-dependent mechanism}},
url = {{http://dx.doi.org/10.3727/096504012x13473664562628}},
doi = {{10.3727/096504012x13473664562628}},
volume = {{20}},
year = {{2012}},
}