Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment

Christina K. Augustine, Yasunori Yoshimoto, Mukur Gupta, Patricia A. Zipfel, M. Angelica Selim, Phillip Febbo, Ann Marie Pendergast, William P. Peters, Douglas Tyler

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Malignant transformation in melanoma is characterized by a phenotype "switch" from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin-expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma.

Original languageEnglish (US)
Pages (from-to)3777-3784
Number of pages8
JournalCancer Research
Volume68
Issue number10
DOIs
StatePublished - May 15 2008
Externally publishedYes

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Melphalan
Cadherins
Melanoma
temozolomide
Drug Therapy
Apoptosis
Fibroblast Growth Factor Receptors
Neoplasms
Focal Adhesions
DNA Adducts
Therapeutics
Heterografts
Extremities
Animal Models
Phenotype
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Augustine, C. K., Yoshimoto, Y., Gupta, M., Zipfel, P. A., Selim, M. A., Febbo, P., ... Tyler, D. (2008). Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. Cancer Research, 68(10), 3777-3784. https://doi.org/10.1158/0008-5472.CAN-07-5949

Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. / Augustine, Christina K.; Yoshimoto, Yasunori; Gupta, Mukur; Zipfel, Patricia A.; Selim, M. Angelica; Febbo, Phillip; Pendergast, Ann Marie; Peters, William P.; Tyler, Douglas.

In: Cancer Research, Vol. 68, No. 10, 15.05.2008, p. 3777-3784.

Research output: Contribution to journalArticle

Augustine, CK, Yoshimoto, Y, Gupta, M, Zipfel, PA, Selim, MA, Febbo, P, Pendergast, AM, Peters, WP & Tyler, D 2008, 'Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment', Cancer Research, vol. 68, no. 10, pp. 3777-3784. https://doi.org/10.1158/0008-5472.CAN-07-5949
Augustine CK, Yoshimoto Y, Gupta M, Zipfel PA, Selim MA, Febbo P et al. Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. Cancer Research. 2008 May 15;68(10):3777-3784. https://doi.org/10.1158/0008-5472.CAN-07-5949
Augustine, Christina K. ; Yoshimoto, Yasunori ; Gupta, Mukur ; Zipfel, Patricia A. ; Selim, M. Angelica ; Febbo, Phillip ; Pendergast, Ann Marie ; Peters, William P. ; Tyler, Douglas. / Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. In: Cancer Research. 2008 ; Vol. 68, No. 10. pp. 3777-3784.
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