Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma

Alaa Al-Tahan, Omar Sarkis, Mohamad Harajly, Omar Kebbe Baghdadi, Kazem Zibara, Fouad Boulos, Dipti Dighe, Steven Kregel, Ali Bazarbachi, Marwan El-Sabban, Stephen X. Skapek, Raya Saab

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation. Procedure: We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts. Results: ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation. Conclusion: Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.

Original languageEnglish (US)
Pages (from-to)877-884
Number of pages8
JournalPediatric Blood and Cancer
Volume58
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Rhabdomyosarcoma
Cell Cycle Checkpoints
Tretinoin
Retinoids
Residual Neoplasm
Heterografts
Alveolar Rhabdomyosarcoma
Cell Proliferation
Skeletal Myoblasts
Embryonal Rhabdomyosarcoma
Myogenin
Therapeutics
Cell Line
Muscles
SCID Mice
Myoblasts
Neuroblastoma
Sarcoma
Neoplasms
Phenotype

Keywords

  • Differentiation
  • Minimal residual disease
  • Retinoic acid
  • Rhabdomyosarcoma
  • Therapy
  • Xenograft

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Al-Tahan, A., Sarkis, O., Harajly, M., Baghdadi, O. K., Zibara, K., Boulos, F., ... Saab, R. (2012). Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma. Pediatric Blood and Cancer, 58(6), 877-884. https://doi.org/10.1002/pbc.23246

Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma. / Al-Tahan, Alaa; Sarkis, Omar; Harajly, Mohamad; Baghdadi, Omar Kebbe; Zibara, Kazem; Boulos, Fouad; Dighe, Dipti; Kregel, Steven; Bazarbachi, Ali; El-Sabban, Marwan; Skapek, Stephen X.; Saab, Raya.

In: Pediatric Blood and Cancer, Vol. 58, No. 6, 06.2012, p. 877-884.

Research output: Contribution to journalArticle

Al-Tahan, A, Sarkis, O, Harajly, M, Baghdadi, OK, Zibara, K, Boulos, F, Dighe, D, Kregel, S, Bazarbachi, A, El-Sabban, M, Skapek, SX & Saab, R 2012, 'Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma', Pediatric Blood and Cancer, vol. 58, no. 6, pp. 877-884. https://doi.org/10.1002/pbc.23246
Al-Tahan, Alaa ; Sarkis, Omar ; Harajly, Mohamad ; Baghdadi, Omar Kebbe ; Zibara, Kazem ; Boulos, Fouad ; Dighe, Dipti ; Kregel, Steven ; Bazarbachi, Ali ; El-Sabban, Marwan ; Skapek, Stephen X. ; Saab, Raya. / Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma. In: Pediatric Blood and Cancer. 2012 ; Vol. 58, No. 6. pp. 877-884.
@article{7e3ae4fcade74db4bc304d3bf2d5c63d,
title = "Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma",
abstract = "Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation. Procedure: We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts. Results: ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation. Conclusion: Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.",
keywords = "Differentiation, Minimal residual disease, Retinoic acid, Rhabdomyosarcoma, Therapy, Xenograft",
author = "Alaa Al-Tahan and Omar Sarkis and Mohamad Harajly and Baghdadi, {Omar Kebbe} and Kazem Zibara and Fouad Boulos and Dipti Dighe and Steven Kregel and Ali Bazarbachi and Marwan El-Sabban and Skapek, {Stephen X.} and Raya Saab",
year = "2012",
month = "6",
doi = "10.1002/pbc.23246",
language = "English (US)",
volume = "58",
pages = "877--884",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma

AU - Al-Tahan, Alaa

AU - Sarkis, Omar

AU - Harajly, Mohamad

AU - Baghdadi, Omar Kebbe

AU - Zibara, Kazem

AU - Boulos, Fouad

AU - Dighe, Dipti

AU - Kregel, Steven

AU - Bazarbachi, Ali

AU - El-Sabban, Marwan

AU - Skapek, Stephen X.

AU - Saab, Raya

PY - 2012/6

Y1 - 2012/6

N2 - Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation. Procedure: We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts. Results: ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation. Conclusion: Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.

AB - Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been shown to induce differentiation in a variety of cells including skeletal myoblasts and neuroblasts. In the setting of minimal residual disease, retinoic acid improves survival in neuroblastoma, another poorly differentiated childhood tumor. Whether such an approach is useful for rhabdomyosarcoma has not yet been investigated. Several in vitro studies have demonstrated an appreciable effect of retinoic acid on human RMS cellular proliferation and differentiation. Procedure: We assessed the efficacy of ATRA on rhabdomyosarcoma, in vitro and in vivo, using cell lines and xenografts. Results: ATRA slowed RMS cell proliferation, and promoted a more differentiated myogenic phenotype in both alveolar and embryonal RMS cell lines. Treatment of cultured murine myoblasts with retinoids increased Myogenin expression, but did not induce cell cycle arrest. Despite the favorable in vitro effects, ATRA failed to delay relapse of minimal residual disease using human RMS xenografts in immuno-suppressed NOD-SCID (NSG) mice. Interestingly, tumors that recurred after ATRA treatment showed evidence of enhanced muscle differentiation. Conclusion: Our results indicate that ATRA could increase the expression of some genes associated with muscle differentiation in rhabdomyosarcoma cells, but there was no benefit of single-agent therapy in an MRD model, likely because cell cycle arrest was uncoupled from the pro-differentiation effects of retinoids.

KW - Differentiation

KW - Minimal residual disease

KW - Retinoic acid

KW - Rhabdomyosarcoma

KW - Therapy

KW - Xenograft

UR - http://www.scopus.com/inward/record.url?scp=84858661687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858661687&partnerID=8YFLogxK

U2 - 10.1002/pbc.23246

DO - 10.1002/pbc.23246

M3 - Article

C2 - 21755593

AN - SCOPUS:84858661687

VL - 58

SP - 877

EP - 884

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 6

ER -