Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma

Ryan S. Turley, Yoshihiro Tokuhisa, Hiroaki Toshimitsu, Michael E. Lidsky, James C. Padussis, Andrew Fontanella, Wanleng Deng, Christina K. Augustine, Georgia M. Beasley, Michael A. Davies, Mark W. Dewhirst, Douglas Tyler

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Original languageEnglish (US)
Pages (from-to)368-377
Number of pages10
JournalAnnals of Surgery
Volume261
Issue number2
DOIs
StatePublished - 2015
Externally publishedYes

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temozolomide
Capillary Permeability
Cadherins
Melanoma
Neoplasms
Extremities
Extracellular Fluid
Heterografts
Phosphatidylinositol 3-Kinase
Pressure
Drug Therapy
Protein Array Analysis
Evans Blue
Melphalan
DNA Adducts
Alkylating Agents
Growth
DNA Damage
Blood Vessels
Permeability

Keywords

  • AKT
  • Drug delivery and N-cadherin
  • Isolated limb infusion
  • Melanoma
  • Vascular permeability

ASJC Scopus subject areas

  • Surgery

Cite this

Turley, R. S., Tokuhisa, Y., Toshimitsu, H., Lidsky, M. E., Padussis, J. C., Fontanella, A., ... Tyler, D. (2015). Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma. Annals of Surgery, 261(2), 368-377. https://doi.org/10.1097/SLA.0000000000000635

Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma. / Turley, Ryan S.; Tokuhisa, Yoshihiro; Toshimitsu, Hiroaki; Lidsky, Michael E.; Padussis, James C.; Fontanella, Andrew; Deng, Wanleng; Augustine, Christina K.; Beasley, Georgia M.; Davies, Michael A.; Dewhirst, Mark W.; Tyler, Douglas.

In: Annals of Surgery, Vol. 261, No. 2, 2015, p. 368-377.

Research output: Contribution to journalArticle

Turley, RS, Tokuhisa, Y, Toshimitsu, H, Lidsky, ME, Padussis, JC, Fontanella, A, Deng, W, Augustine, CK, Beasley, GM, Davies, MA, Dewhirst, MW & Tyler, D 2015, 'Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma', Annals of Surgery, vol. 261, no. 2, pp. 368-377. https://doi.org/10.1097/SLA.0000000000000635
Turley RS, Tokuhisa Y, Toshimitsu H, Lidsky ME, Padussis JC, Fontanella A et al. Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma. Annals of Surgery. 2015;261(2):368-377. https://doi.org/10.1097/SLA.0000000000000635
Turley, Ryan S. ; Tokuhisa, Yoshihiro ; Toshimitsu, Hiroaki ; Lidsky, Michael E. ; Padussis, James C. ; Fontanella, Andrew ; Deng, Wanleng ; Augustine, Christina K. ; Beasley, Georgia M. ; Davies, Michael A. ; Dewhirst, Mark W. ; Tyler, Douglas. / Targeting n-cadherin increases vascular permeability and differentially activates akt in melanoma. In: Annals of Surgery. 2015 ; Vol. 261, No. 2. pp. 368-377.
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abstract = "Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.",
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AU - Turley, Ryan S.

AU - Tokuhisa, Yoshihiro

AU - Toshimitsu, Hiroaki

AU - Lidsky, Michael E.

AU - Padussis, James C.

AU - Fontanella, Andrew

AU - Deng, Wanleng

AU - Augustine, Christina K.

AU - Beasley, Georgia M.

AU - Davies, Michael A.

AU - Dewhirst, Mark W.

AU - Tyler, Douglas

PY - 2015

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N2 - Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

AB - Objective: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma. Background: N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects. Methods: Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis. Results: Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ. Conclusions: ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

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KW - Melanoma

KW - Vascular permeability

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