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Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression.

Klopper JP, Sharma V, Berenz A, Hays WR, Loi M, Pugazhenthi U, Said S, Haugen BR - Mol. Cancer (2009)

Bottom Line: A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect.A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells.Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5-16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRgamma resulted in a decreased response to either ligand.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO, USA. joshua.klopper@ucdenver.edu

ABSTRACT

Background: Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid x receptor selective agonist, and thiazolidinediones (TZD), PPARgamma selective ligands, as novel treatments.

Results: Mouse xenograft models with human melanoma cell lines [A375(DRO) or M14(5-16)] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d), PPARgamma agonist (TZD, rosiglitazone, 10 mg/kg/d) or combination. A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5-16) tumors only responded to LGD1069 100 mg/kg/day. A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells. Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5-16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRgamma resulted in a decreased response to either ligand.

Conclusion: A375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARgamma receptor expression. M14 (5-16) melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

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1a: In vivo tumor response of A375(DRO) xenograft tumors. 5 × 106 A375(DRO) cells were injected s.c. and tumors were allowed to grow for 3.5 wk after tumor establishment (~100 mm3). After estblishment, treatment conditions were (A) control, (B) 30 mg/kg/d LGD1069, and (C) 10 mg/kg/d ROSI and (D) combination of 30 mg/kg/day LGD1069 and 10 mg/kg/day ROSI. Tumors were measured twice per week. Points, mean tumor volume/group; bars, SEM. One Way ANOVA – Kruskal-Wallis test was used to assess the significance of the difference of tumor sizes at the end of the experiment (*P = 0.002). 1b: representative control tumor showing approximately 20% necrosis (*). Marked cellular vacuolization is seen in the non-necrotic tissue. Hematoxyline and Eosin staining 2× magnification. 1c: An enlarged picture from the control tumor showing the junction of the necrotic (*) and the viable, yet markedly vacuolated melanoma cells. Hematoxyline and Eosin staining. 40× magnification. 1d: A representative Rosi treated tumor with > 70% necrosis (edged by arrows) of the total tissue volume with a small rim of viable tumor. Hematoxyline and Eosin staining 2× magnification.
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Figure 1: 1a: In vivo tumor response of A375(DRO) xenograft tumors. 5 × 106 A375(DRO) cells were injected s.c. and tumors were allowed to grow for 3.5 wk after tumor establishment (~100 mm3). After estblishment, treatment conditions were (A) control, (B) 30 mg/kg/d LGD1069, and (C) 10 mg/kg/d ROSI and (D) combination of 30 mg/kg/day LGD1069 and 10 mg/kg/day ROSI. Tumors were measured twice per week. Points, mean tumor volume/group; bars, SEM. One Way ANOVA – Kruskal-Wallis test was used to assess the significance of the difference of tumor sizes at the end of the experiment (*P = 0.002). 1b: representative control tumor showing approximately 20% necrosis (*). Marked cellular vacuolization is seen in the non-necrotic tissue. Hematoxyline and Eosin staining 2× magnification. 1c: An enlarged picture from the control tumor showing the junction of the necrotic (*) and the viable, yet markedly vacuolated melanoma cells. Hematoxyline and Eosin staining. 40× magnification. 1d: A representative Rosi treated tumor with > 70% necrosis (edged by arrows) of the total tissue volume with a small rim of viable tumor. Hematoxyline and Eosin staining 2× magnification.

Mentions: LGD1069 and ROSI treatments alone each had a modest effect on tumor growth (figs. 1a, 52% and 36% smaller than control respectively). Combination LGD1069 and ROSI inhibited tumor growth by 73% compared with controls. All tumor sizes at the end of the treatment were significantly smaller that untreated mice (p = 0.002, 1-way ANOVA Kruskal-Wallis method).


Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression.

Klopper JP, Sharma V, Berenz A, Hays WR, Loi M, Pugazhenthi U, Said S, Haugen BR - Mol. Cancer (2009)

1a: In vivo tumor response of A375(DRO) xenograft tumors. 5 × 106 A375(DRO) cells were injected s.c. and tumors were allowed to grow for 3.5 wk after tumor establishment (~100 mm3). After estblishment, treatment conditions were (A) control, (B) 30 mg/kg/d LGD1069, and (C) 10 mg/kg/d ROSI and (D) combination of 30 mg/kg/day LGD1069 and 10 mg/kg/day ROSI. Tumors were measured twice per week. Points, mean tumor volume/group; bars, SEM. One Way ANOVA – Kruskal-Wallis test was used to assess the significance of the difference of tumor sizes at the end of the experiment (*P = 0.002). 1b: representative control tumor showing approximately 20% necrosis (*). Marked cellular vacuolization is seen in the non-necrotic tissue. Hematoxyline and Eosin staining 2× magnification. 1c: An enlarged picture from the control tumor showing the junction of the necrotic (*) and the viable, yet markedly vacuolated melanoma cells. Hematoxyline and Eosin staining. 40× magnification. 1d: A representative Rosi treated tumor with > 70% necrosis (edged by arrows) of the total tissue volume with a small rim of viable tumor. Hematoxyline and Eosin staining 2× magnification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654861&req=5

Figure 1: 1a: In vivo tumor response of A375(DRO) xenograft tumors. 5 × 106 A375(DRO) cells were injected s.c. and tumors were allowed to grow for 3.5 wk after tumor establishment (~100 mm3). After estblishment, treatment conditions were (A) control, (B) 30 mg/kg/d LGD1069, and (C) 10 mg/kg/d ROSI and (D) combination of 30 mg/kg/day LGD1069 and 10 mg/kg/day ROSI. Tumors were measured twice per week. Points, mean tumor volume/group; bars, SEM. One Way ANOVA – Kruskal-Wallis test was used to assess the significance of the difference of tumor sizes at the end of the experiment (*P = 0.002). 1b: representative control tumor showing approximately 20% necrosis (*). Marked cellular vacuolization is seen in the non-necrotic tissue. Hematoxyline and Eosin staining 2× magnification. 1c: An enlarged picture from the control tumor showing the junction of the necrotic (*) and the viable, yet markedly vacuolated melanoma cells. Hematoxyline and Eosin staining. 40× magnification. 1d: A representative Rosi treated tumor with > 70% necrosis (edged by arrows) of the total tissue volume with a small rim of viable tumor. Hematoxyline and Eosin staining 2× magnification.
Mentions: LGD1069 and ROSI treatments alone each had a modest effect on tumor growth (figs. 1a, 52% and 36% smaller than control respectively). Combination LGD1069 and ROSI inhibited tumor growth by 73% compared with controls. All tumor sizes at the end of the treatment were significantly smaller that untreated mice (p = 0.002, 1-way ANOVA Kruskal-Wallis method).

Bottom Line: A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect.A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells.Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5-16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRgamma resulted in a decreased response to either ligand.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO, USA. joshua.klopper@ucdenver.edu

ABSTRACT

Background: Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid x receptor selective agonist, and thiazolidinediones (TZD), PPARgamma selective ligands, as novel treatments.

Results: Mouse xenograft models with human melanoma cell lines [A375(DRO) or M14(5-16)] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d), PPARgamma agonist (TZD, rosiglitazone, 10 mg/kg/d) or combination. A375(DRO) tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5-16) tumors only responded to LGD1069 100 mg/kg/day. A375(DRO) sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARgamma expression but preserved RXR expression. shRNA knockdown of PPARgamma or RXRgamma attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO) cells. Rexinoid (LGD1069) and retinoid (TTNPB) treatment of M14(5-16) cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRgamma resulted in a decreased response to either ligand.

Conclusion: A375 (DRO) melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARgamma receptor expression. M14 (5-16) melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

Show MeSH
Related in: MedlinePlus