Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells

M. Danielle Bareford, Hossein A. Hamed, Yong Tang, Nichola Cruickshanks, Matthew E. Burow, Paul B. Fisher, Richard G. Moran, Kenneth Nephew, Steven Grant, Paul Dent

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Pemetrexed (ALIMTA) is a folate antimetabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.

Original languageEnglish
Pages (from-to)1261-1262
Number of pages2
JournalAutophagy
Volume7
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Pemetrexed
Autophagy
Neoplasms
Animal Mammary Neoplasms
Antimetabolites
sorafenib
Poisons
Glioblastoma
Folic Acid
Heterografts
Non-Small Cell Lung Carcinoma
Hepatocellular Carcinoma
Animal Models

Keywords

  • AMP
  • Apoptosis
  • Autophagy
  • PDGFR
  • Pemetrexed
  • Sorafenib
  • Thymidylate synthase
  • ZMP

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Bareford, M. D., Hamed, H. A., Tang, Y., Cruickshanks, N., Burow, M. E., Fisher, P. B., ... Dent, P. (2011). Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Autophagy, 7(10), 1261-1262. https://doi.org/10.4161/auto.7.10.17029

Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. / Bareford, M. Danielle; Hamed, Hossein A.; Tang, Yong; Cruickshanks, Nichola; Burow, Matthew E.; Fisher, Paul B.; Moran, Richard G.; Nephew, Kenneth; Grant, Steven; Dent, Paul.

In: Autophagy, Vol. 7, No. 10, 10.2011, p. 1261-1262.

Research output: Contribution to journalArticle

Bareford, MD, Hamed, HA, Tang, Y, Cruickshanks, N, Burow, ME, Fisher, PB, Moran, RG, Nephew, K, Grant, S & Dent, P 2011, 'Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells', Autophagy, vol. 7, no. 10, pp. 1261-1262. https://doi.org/10.4161/auto.7.10.17029
Bareford MD, Hamed HA, Tang Y, Cruickshanks N, Burow ME, Fisher PB et al. Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Autophagy. 2011 Oct;7(10):1261-1262. https://doi.org/10.4161/auto.7.10.17029
Bareford, M. Danielle ; Hamed, Hossein A. ; Tang, Yong ; Cruickshanks, Nichola ; Burow, Matthew E. ; Fisher, Paul B. ; Moran, Richard G. ; Nephew, Kenneth ; Grant, Steven ; Dent, Paul. / Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. In: Autophagy. 2011 ; Vol. 7, No. 10. pp. 1261-1262.
@article{829f9d152d5f4ecdb16bd565fbeb1a4a,
title = "Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells",
abstract = "Pemetrexed (ALIMTA) is a folate antimetabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.",
keywords = "AMP, Apoptosis, Autophagy, PDGFR, Pemetrexed, Sorafenib, Thymidylate synthase, ZMP",
author = "Bareford, {M. Danielle} and Hamed, {Hossein A.} and Yong Tang and Nichola Cruickshanks and Burow, {Matthew E.} and Fisher, {Paul B.} and Moran, {Richard G.} and Kenneth Nephew and Steven Grant and Paul Dent",
year = "2011",
month = "10",
doi = "10.4161/auto.7.10.17029",
language = "English",
volume = "7",
pages = "1261--1262",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "10",

}

TY - JOUR

T1 - Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells

AU - Bareford, M. Danielle

AU - Hamed, Hossein A.

AU - Tang, Yong

AU - Cruickshanks, Nichola

AU - Burow, Matthew E.

AU - Fisher, Paul B.

AU - Moran, Richard G.

AU - Nephew, Kenneth

AU - Grant, Steven

AU - Dent, Paul

PY - 2011/10

Y1 - 2011/10

N2 - Pemetrexed (ALIMTA) is a folate antimetabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.

AB - Pemetrexed (ALIMTA) is a folate antimetabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.

KW - AMP

KW - Apoptosis

KW - Autophagy

KW - PDGFR

KW - Pemetrexed

KW - Sorafenib

KW - Thymidylate synthase

KW - ZMP

UR - http://www.scopus.com/inward/record.url?scp=80053422885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053422885&partnerID=8YFLogxK

U2 - 10.4161/auto.7.10.17029

DO - 10.4161/auto.7.10.17029

M3 - Article

C2 - 21814046

AN - SCOPUS:80053422885

VL - 7

SP - 1261

EP - 1262

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 10

ER -