Researchers characterized the activity of a heat shock protein 90 (HSP90) inhibitor and a plant-derived coumarin against a myelodysplastic syndrome (MDS) cell line, and they found inhibition of cell proliferation and induction of apoptosis in tumor cells with this combination. They reported their results which were published in the journal Experimental and Therapeutic Medicine.
The researchers explained in their report that cell proliferation and tumorigenesis can result from the activation of telomerase and that binding of HSP90 to human telomerase reverse transcriptase (hTERT) may contribute to this activation. Higher-risk MDS is associated with increased expression of HSP90, according to the researchers.
The plant-derived coumarin, called HDE, used in this study was an ethyl acetate extract derived from the plant species Oldenlandia diffusa Willd. In this study, the researchers examined the effect on MDS cells by treatment with an HSP90 inhibitor, BIIB021, and the potentially anti-inflammatory HDE.
The MDS cell line the researchers used was the SKM-1 cell line. In addition to treating the cells with HDE and BIIB021, the researchers also transfected cells with small interfering RNA (siRNA) sequences targeting hTERT. Assays were performed to measure telomerase activity, HSP90 expression, and other effects on cells.
The researchers measured the effects on SKM-1 cell proliferation of a range of concentrations of HDE and BIIB021 and chose concentrations of 98.03 mg/mL of HDE and 171.7 nmol/L of BIIB021 for use in further experiments. Cell proliferation was reportedly inhibited with either HDE or BIIB021, compared with a control treatment (P <.01 for each comparison). The combination of HDE and BIIB021 appeared to further inhibit cell proliferation (P <.01).
Telomerase activity and HSP90 expression both occurred at significantly higher levels in the SKM-1 cell line in comparison with bone marrow-derived stem cells. Telomerase activity in SKM-1 cells appeared to be suppressed in the presence of HDE or BIIB021, and especially with the combination (P <.01 for each comparison). HDE, BIIB021, and the combination also significantly reduced HSP90 expression in SKM-1 cells (P <.05 for each comparison).
Additionally, the treatment of SKM-1 cells with HDE and BIIB021 reportedly induced apoptosis, and when siRNA targeting hTERT was added to this treatment combination, apoptosis appeared to be enhanced further (P <.01 for each comparison).
“In conclusion, the present study identified a new active component HDE in Oldenlandia diffusa Willd, which displayed apoptosis‑inducing effects on the MDS‑derived leukemia cell line SKM‑1, and the underlying mechanism, which involved downregulation of hTERT expression,” the researchers wrote in their report.
Wang B, Jiang J, Zhang Y, et al. Combination of HDE and BIIB021 efficiently inhibits cell proliferation and induces apoptosis via downregulating hTERT in myelodysplastic syndromes. Exp Ther Med. 2021;21(5):503. doi:10.3892/etm.2021.9934