Inhibition of mouse embryonic carcinoma cell growth by lidamycin through down-regulation of embryonic stem cell-like genes Oct4, Sox2 and Myc

Abstract

Lidamycin (LDM, also known as C-1027) as an anti-cancer agent inhibits growth in a variety of cancer cells by inducing apoptosis and cell cycle arrest. In this study we demonstrated that inhibition of mouse embryonic carcinoma (EC) cell growth using LDM at low concentrations can be attributed to a loss of the cell's self-renewal capability but not to apoptosis or cell death, which can be correlated to the down-regulation of embryonic stem (ES) cell-like genes Oct4, Sox2 and c-Myc. MTT assays showed that LDM inhibited the growth of mouse P19 EC cells in a time- and dose-dependent manner. The EC cells exposed to a low dose (0.01 nM) of LDM lost their capability to generate colonies, as evidenced by the colony forming assay. Flow cytometer analyses demonstrated that LDM induced G1 arrest in exposed EC cells without apoptosis. Real-time qPCR, Western blotting and immunocytochemistry revealed that Oct4, Sox2 and c-Myc were down-regulated in LDM-exposed EC cells, but not adriamycin (ADM)-exposed cells. Furthermore, a combination of the low dose of LDM and ADM significantly reduced the proliferation of the cancer cells than single-agent treatment. This suggested that synergy of ADM and LDM improved chemotherapy. Taking together, our results indicate that LDM can reduce the capability for self-renewal that mouse EC cells possess through the repression of ES cell-like genes, thereby inhibiting carcinoma cell growth. This data also suggests that LDM might have potential for application in CSC-based therapy and be a useful tool for studying ES cell pluripotency and differentiation.

Lidamycin inhibits tumor initiating cells of hepatocellular carcinoma Huh7 through GSK3β/β‐catenin pathway

“…LDM has been proved to display the potent antitumor effects in HCC [10,28]. Recent studies showed that LDM reduced the capability of self-renewal through downregula-tion of embryonic stem cell-like genes [13]. Therefore, we detected the effects of LDM on TICs in HCC.…”

Lidamycin decreases CD133 expression in hepatocellular carcinoma via the Notch signaling pathway

“…In a previous study, LDM was revealed to downregulate embryonic stem cell-like genes: Octamer-binding transcription factor 4, SRY-box 2 and MYC proto-oncogene (23). Additionally, LDM has been demonstrated to decreases the expression of EpCAM, aldehyde dehydrogenase-positive cells, sphere formation in vitro, and inhibit tumor volume and incidence in vivo; this suggests that LDM may suppress Huh7 tumor initiating cells (15).…”

“…the levels of embryonic stem cell-like genes (23). In addition, LDM inhibits EpCAM + tumor initiating cells through the GSK3β/β-catenin signaling pathway in HCC (15).…”

The novel structure make LDM effectively remove CD123+ AML stem cells in combination with interleukin 3

“…24 It was important that low concentrations LDM could also down-regulated embryonic stem (ES) cell-like genes Oct4, Sox2 and c-Myc. 25 LSCs are not sensitive to conventional chemotherapy drugs because they usually stay in the resting period. That suggests that LDM has better effection on LSCs.…”

“…Even more interestingly, LDM downregulated the genes related to stem cells including Oct4, Sox2 and Myc so that it inhibited mouse embryonic carcinoma ( EC ) cell growth. 25 It preferred to weak cell self-renewal ability rather than cause cell apoptosis or death. Sensitivity to the stem cells or stem like cells made LDM more suitable for application in LSC-targeted therapy.…”