WYC-209, a RAR Agonist, Induces TRCs Apoptosis with Low Toxicity

Chemotherapy is one of the principal modes of treatment for cancer. However, resistance to chemotherapeutic drugs is a hallmark of malignant tumors that results in major limitation in chemotherapy. Cancer stem cells (CSCs) or tumor-initiating cells (TICs) play a critical role in the initiation and progression of cancer. In this study, the author develops 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. As a consequence, they functionally those define soft-fibrin-gel-selected cancer cells as tumor-repopulating cells (TRCs). These TRCs express high levels of self-renewing gene Sox2 and low levels of master differentiation gene Mitf. Hence, they appear to remain undifferentiated or partially differentiated.

Here, the author describes a novel synthetic retinoid, WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs). WYC-209 displays an IC50 of 0.19 μM in a dose-dependent manner. Meanwhile, WYC-209 targets the molecule is retinoic acid receptor.

WYC 209 a RAR Agonist Induces TRCs Apoptosis with Low Toxicity 2019 07 13 - WYC-209, a RAR Agonist, Induces TRCs Apoptosis with Low Toxicity

In vitro, the effect of WYC-209 is long lasting and there is no sign of “relapse” in this in vitro cell culture model. WYC-209 treats in five different human cancer cell lines, including ovarian carcinoma A2780, lung adenocarcinoma A549, breast cancer MCF-7, melanoma MDA-MB-435s, and malignant melanoma A375, which inhibits all five types of TRCs in a dose-dependent manner when the compound was added on day 3. Further study finds that WYC-209 can abrogate TRC growth by inducing TRC apoptosis, and it induces TRCs apoptosis primarily via the caspase 3 pathway.

In vivo, WYC-209 inhibits tumor metastasis in C57BL/6 mice bearing lung metastases. Moreover, WYC-209 appears to have little toxic effects in cultured non-cancerous murine 3T3 fibroblasts.

All in all, the retinoid WYC-209 has high efficacy and little toxicity in treating malignant melanoma tumors.

Reference:

Chen J, et al. Inhibition of cancer stem cell like cells by a synthetic retinoid. Nat Commun. 2018 Apr 11;9(1):1406.