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Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis
Published on: May 12, 2019
HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids
Di-Wei Tang1, I-Chung Chen1, Po-Yu Chou1
1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Abstract:
The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.
Insights
Novel dual inhibitors targeting HSP90 and LSD1 show significant anti-cancer effects in prostate and colorectal cancers. Compound 6 effectively reduced tumor growth and improved chemotherapy sensitivity, offering new therapeutic potential.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Targeting Heat Shock Protein 90 (HSP90) and Lysine-Specific Demethylase 1 (LSD1) offers a promising strategy for cancer therapy.
- Developing novel inhibitors with dual targeting capabilities can enhance anti-cancer efficacy.
Purpose of the Study:
- To design and synthesize novel hybrid inhibitors targeting both HSP90 and LSD1 axes.
- To evaluate the anti-proliferative activity and mechanism of action of these inhibitors in prostate and colorectal cancer models.
Main Methods:
- Synthesis of hybrid molecules incorporating pharmacophores for HSP90 and LSD1.
- In vitro anti-proliferative assays using prostate cancer cell lines (PC-3, DU145) and colorectal cancer (CRC) organoids.
- Analysis of apoptosis-related signaling pathways (PARP, γH2AX, caspase, Bcl-xL/Bax).
- In vivo safety assessment in zebrafish models.
Main Results:
- Inhibitor 6 demonstrated potent anti-proliferative activity against PC-3 and DU145 cells (GI50 values 0.24 and 0.30 μM).
- Compound 6 induced apoptosis via PARP and γH2AX signaling in a caspase-dependent manner.
- Significant efficacy was observed in docetaxel-resistant PC-3 cells, improving docetaxel sensitivity.
- Compound 6 inhibited patient-derived CRC organoid growth in vitro.
Conclusions:
- The designed HSP90/LSD1 inhibitors exhibit significant anti-cancer capacity.
- Compound 6 presents a novel therapeutic candidate with dual inhibitory action and potential clinical value for prostate and colorectal cancers.
