Related Experiment Video
Updated: Aug 23, 2026
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice
Sylvia S W Ng1, Gordon R MacPherson, Michael Gütschow
1Molecular Pharmacology Section, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Purpose:
Thalidomide has demonstrated clinical activity in various malignancies including androgen-independent prostate cancer. The development of novel thalidomide analogs with better activity/toxicity profiles is an ongoing research effort. Our laboratory previously reported the in vitro antiangiogenic activity of the N-substituted thalidomide analog CPS11 and the tetrafluorinated analogs CPS45 and CPS49. The current study evaluated the therapeutic potential of these analogs in the treatment of prostate cancer in vivo.
Experimental Design:
Severely combined immunodeficient mice bearing s.c. human prostate cancer (PC3 or 22Rv1) xenografts were treated with the analogs at their maximum tolerated doses. Tumors were then excised and processed for ELISA and CD31 immunostaining to determine the levels of various angiogenic factors and microvessel density (MVD), respectively.
Results:
CPS11, CPS45, and CPS49 induced prominent and modest growth inhibition in PC3 and 22Rv1 tumors, respectively. Thalidomide had no effect on tumor growth in either xenograft. Vascular endothelial growth factor and basic fibroblast growth factor levels were not significantly altered by any of the thalidomide analogs or thalidomide in both PC3 and 22Rv1 tumors. CPS45, CPS49, and thalidomide significantly reduced PC3 tumor platelet-derived growth factor (PDGF)-AA levels by 58-82% (P < 0.05). Interestingly, treatment with the analogs and thalidomide resulted in differential down-regulation (>/=1.5-fold) of genes encoding PDGF and PDGF receptor isoforms as determined by DNA microarray analysis. Intratumoral MVD of 22Rv1 xenografts was significantly decreased by CPS45 and CPS49. CPS49 also reduced MVD in PC3 xenografts.
Conclusions:
Thalidomide analogs CPS11 and 49 are promising anti-cancer agents. PDGF signaling pathway may be a potential target for these thalidomide analogs. Detailed microarray and functional analyses are under way with the aim of elucidating the molecular mechanism(s) of action of these thalidomide analogs.
Insights
Novel thalidomide analogs, CPS11 and CPS49, show promise in inhibiting prostate cancer growth by targeting the PDGF signaling pathway. These analogs demonstrated significant anti-tumor activity in vivo, unlike thalidomide itself.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Thalidomide exhibits anti-cancer activity, including in prostate cancer.
- Developing thalidomide analogs with improved efficacy and safety is crucial.
- Previous studies showed in vitro antiangiogenic activity for CPS11, CPS45, and CPS49.
Purpose of the Study:
- To evaluate the in vivo therapeutic potential of thalidomide analogs CPS11, CPS45, and CPS49 against prostate cancer.
- To assess the anti-tumor and antiangiogenic effects of these analogs in preclinical models.
Main Methods:
- Human prostate cancer xenografts (PC3, 22Rv1) were established in immunodeficient mice.
- Mice were treated with thalidomide analogs (CPS11, CPS45, CPS49) at maximum tolerated doses.
- Tumor growth, angiogenic factor levels, and microvessel density (MVD) were analyzed.
Main Results:
- CPS11, CPS45, and CPS49 inhibited tumor growth in PC3 and 22Rv1 xenografts.
- Thalidomide showed no significant effect on tumor growth.
- Analogs and thalidomide reduced platelet-derived growth factor (PDGF)-AA levels and downregulated PDGF pathway genes.
- CPS45 and CPS49 significantly decreased MVD in 22Rv1 and PC3 xenografts.
Conclusions:
- Thalidomide analogs CPS11 and CPS49 are effective anti-cancer agents against prostate cancer.
- The PDGF signaling pathway is a potential therapeutic target for these analogs.
- Further research is needed to elucidate the precise molecular mechanisms of action.
