Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo
Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo
复制标题
DOI：
10.1158/1078-0432.ccr-04-2160
复制
发表时间：
2005-07-01
影响因子：
11.5
通讯作者：
Cohen, P
中科院分区：
文献类型：
--
作者：
Liu, BR;Lee, KW;Cohen, P
我们已经发现维甲酸X受体α(RXRα)是胰岛素样生长因子结合蛋白-3(IGFBP-3)的核结合伙伴，它是IGFBP-3诱导细胞凋亡所必需的。在本研究中，我们研究了RXR配体VTP194204和rhIGFBP-3在体内外的生物相互作用。在体外，IGFBP-3和VTP194204分别诱导前列腺癌细胞株的凋亡，并以相加的方式抑制细胞生长。在体内，携带LAPC-4移植瘤的严重联合免疫缺陷小鼠每天用生理盐水、IGFBP-3和/或VTP194204治疗3周，单独使用IGFBP-3或VTP194204对肿瘤生长没有影响。然而，IGFBP-3和VTP194204联合治疗可抑制50%的肿瘤生长，并显著降低血清前列腺特异性抗原水平。在LAPC-4移植瘤的末端核苷酸转移酶介导的缺口末端标记免疫组织化学中，IGFBP-3和VTP 194204单独治疗均可轻度诱导肿瘤细胞凋亡，但联合治疗可导致大量细胞死亡，提示IGFBP-3和VTP 194204通过诱导细胞凋亡来抑制肿瘤生长。综上所述，这是IGFBP-3作为体内肿瘤治疗的成功应用的初步描述，并表明IGFBP-3和RXR配体联合治疗在诱导细胞凋亡方面具有协同作用，从而显著抑制前列腺癌异种移植瘤的生长。综上所述，这些观察结果表明，IGFBP-3和RXR配体联合治疗前列腺癌可能具有治疗潜力。
We have previously identified the retinoid X receptor-alpha (RXR alpha) as an insulin-like growth factor binding protein-3 (IGFBP-3) nuclear binding partner, which is required for IGFBP-3-induced apoptosis. In the current study, we investigated the biological interactions of the RXR ligand, VTP194204 and rhIGFBP-3, in vitro and in vivo. In vitro, IGFBP-3 and VTP194204 individually induced apoptosis, and suppressed cell growth in prostate cancer cell lines in an additive manner. In vivo, LAPC-4 xenograft-bearing severe combined immunodeficiency mice treated daily with saline, IGFBP-3, and/or VTP194204 for 3 weeks showed no effect of individual treatments with IGFBP-3 or VTP194204 on tumor growth. However, the combination of IGFBP-3 and VTP194204 treatments inhibited tumor growth by 50% and induced a significant reduction in serum prostate-specific antigen levels. In terminal nucleotidyl transferase-mediated nick end labeling immunohistochemistry of LAPC-4 xenografts, there was modest induction of apoptosis with either IGFBP-3 or VTP194204 individual treatment, but combination therapy resulted in massive cell death, indicating that IGFBP-3 and VTP194204 have a synergistic effect in preventing tumor growth by apoptosis induction. In summary, this is an initial description of the successful therapeutic use of IGFBP-3 as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer xenograft growth. Taken together, these observations suggest that combination therapy with IGFBP-3 and RXR ligands may have therapeutic potential for prostate cancer treatment.