Retinoid library screening and discovery of WYC-209 In the current study, we describe synthesis and discovery of a novel retinoid, named WYC-209, which abrogates growth of TRCs of several cancer cell lines in culture and inhibits lung metastasis by melanoma TRCs in vivo, with little toxicity on non-cancerous cells or immune-competent mice.
In order to develop highly potent retinoids with great efficiency in inhibition of cancer stem cell like TRCs, we have performed in-house drug discovery processes to specifically overcome these limitations. However, poor water solubility and high toxicity of RA significantly limit its use in clinical treatment of cancer 8, 9, 10, 11. Treating TRCs with retinoid acid (RA), which is a nonspecific differentiation factor, could inhibit TRCs extravasation 7, a key late stage in metastasis. These TRCs express high levels of self-renewing gene Sox2 and low levels of master differentiation gene Mitf and hence appear to remain undifferentiated or partially differentiated 6. We thus functionally define these soft-fibrin-gel-selected cancer cells as tumor-repopulating cells (TRCs), differentiating them from CSCs or TICs that are selected via cell surface stem cell marker approaches. Remarkably, when injected the selected cancer cells into tail veins, as few as ten of such cells can generate distant metastatic colonization in immune-competent mice. The selected cancer cells display high self-renewal ability and are resistant to chemotherapeutic drugs such as cisplatin and doxorubicin 5. We have recently developed a mechanical method of selecting and growing tumorigenic cells from cancer cell lines and primary cancer cells by culturing single cancer cells in soft fibrin gels 5.
As a consequence, developing targeted chemotherapeutic drugs to abrogate CSCs or TICs is a key task in cancer research and clinical application. CSCs or TICs exhibit high chemo-resistance to conventional chemotherapeutic drug treatment and therefore are speculated to be the key players in cancer relapse after chemotherapy 4. They play a critical role in the initiation and progression of cancer 3. Cancer stem cells (CSCs) or tumor-initiating cells (TICs) are a self-renewing, highly tumorigenic subpopulation of tumor cells. Our findings demonstrate the promise of the new retinoid WYC-209 in treating malignant melanoma tumors with high efficacy and little toxicity.Ĭhemotherapy is one of the principal modes of treatment for cancer, but resistance to chemotherapeutic drugs is a hallmark of malignant tumors that results in major limitation in chemotherapy 1, 2. WYC-209 induces TRC apoptosis and pretreating the TRCs with caspase 3 inhibitor or depleting caspase 3 with siRNAs substantially rescues growth of TRCs from WYC-209 inhibition, suggesting that WYC-209 induces TRCs apoptosis primarily via the caspase 3 pathway.
#PROJECT PLAYAZ TILL WE DIE RAR RAR#
Pretreating the melanoma TRCs with retinoic acid receptor (RAR) antagonists or with RAR siRNAs blocks or reduces the inhibitory effect of the molecule, suggesting that the target of the molecule is RAR. Importantly, the molecule abrogates 87.5% of lung metastases of melanoma TRCs in immune-competent wild-type C57BL/6 mice at 0.22 mg kg −1 without showing apparent toxicity. Interestingly, the treated TRCs fail to resume growth even after the drug washout. WYC-209 also inhibits proliferation of TRCs of human melanoma, lung cancer, ovarian cancer, and breast cancer in culture. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC 50 of 0.19 μM in a dose-dependent manner. Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers.
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