Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents

Wenge Wang, Jean Nicolas Gallant, Sharyn I. Katz, Nathan G. Dolloff, Charles D. Smith, Junaid Abdulghani, Joshua E. Allen, David T. Dicker, Bo Hong, Arunasalam Navaraj, Wafik S. El-Deiry

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 μM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. however, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Of particular interest, combination of quinacrine and sorefnib, can effectively eradicate Mcl-1 and sensitizes HepG2 cells to TRAIL both in vitro and in vivo. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.

Original languageEnglish (US)
Pages (from-to)229-238
Number of pages10
JournalCancer Biology and Therapy
Volume12
Issue number3
DOIs
StatePublished - Aug 1 2011

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Quinacrine
Hepatocellular Carcinoma
Cell Death
Hep G2 Cells
gemcitabine
Therapeutics
Giardiasis
Death Domain Receptors
Etoposide
Rheumatic Diseases
Fluorouracil
Doxorubicin
Small Interfering RNA
Malaria

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Wang, W., Gallant, J. N., Katz, S. I., Dolloff, N. G., Smith, C. D., Abdulghani, J., ... El-Deiry, W. S. (2011). Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents. Cancer Biology and Therapy, 12(3), 229-238. https://doi.org/10.4161/cbt.12.3.17033
Wang, Wenge ; Gallant, Jean Nicolas ; Katz, Sharyn I. ; Dolloff, Nathan G. ; Smith, Charles D. ; Abdulghani, Junaid ; Allen, Joshua E. ; Dicker, David T. ; Hong, Bo ; Navaraj, Arunasalam ; El-Deiry, Wafik S. / Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents. In: Cancer Biology and Therapy. 2011 ; Vol. 12, No. 3. pp. 229-238.
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abstract = "Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 μM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. however, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Of particular interest, combination of quinacrine and sorefnib, can effectively eradicate Mcl-1 and sensitizes HepG2 cells to TRAIL both in vitro and in vivo. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.",
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Wang, W, Gallant, JN, Katz, SI, Dolloff, NG, Smith, CD, Abdulghani, J, Allen, JE, Dicker, DT, Hong, B, Navaraj, A & El-Deiry, WS 2011, 'Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents', Cancer Biology and Therapy, vol. 12, no. 3, pp. 229-238. https://doi.org/10.4161/cbt.12.3.17033

Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents. / Wang, Wenge; Gallant, Jean Nicolas; Katz, Sharyn I.; Dolloff, Nathan G.; Smith, Charles D.; Abdulghani, Junaid; Allen, Joshua E.; Dicker, David T.; Hong, Bo; Navaraj, Arunasalam; El-Deiry, Wafik S.

In: Cancer Biology and Therapy, Vol. 12, No. 3, 01.08.2011, p. 229-238.

Research output: Contribution to journalArticle

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T1 - Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents

AU - Wang, Wenge

AU - Gallant, Jean Nicolas

AU - Katz, Sharyn I.

AU - Dolloff, Nathan G.

AU - Smith, Charles D.

AU - Abdulghani, Junaid

AU - Allen, Joshua E.

AU - Dicker, David T.

AU - Hong, Bo

AU - Navaraj, Arunasalam

AU - El-Deiry, Wafik S.

PY - 2011/8/1

Y1 - 2011/8/1

N2 - Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by quinacrine alone at concentrations of 10-20 μM for 1-2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. however, quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death within 3-4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism by which quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapies, and the potential for clinical application currently are being further explored. Of particular interest, combination of quinacrine and sorefnib, can effectively eradicate Mcl-1 and sensitizes HepG2 cells to TRAIL both in vitro and in vivo. Lastly, quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo.

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