Geldanamycin and its analog induce growth arrest of cultured human retinal pigment epithelial cells

1. Wen-Chuan Wu¹
2. Meng-Hsien Wu¹
3. Yo-Chen Chang^1,2
4. Horng-Jiun Wu^1,2
5. Yu-Hung Lai^1,2
6. Ying-Hsien Kao³

¹Departments of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
²Department of Ophthalmology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
³Department of Medical Research, E-DA Hospital, I-Shou University, Kaohsiung County, Taiwan

Geldanamycin (GA) and its analogs, including 17-allylamino-demethoxy geldanamycin (17-AAG), block the function of a molecular chaperone, heat shock protein 90 (Hsp90). They pharmacologically possess anti-tumor properties through its direct cytotoxicity on tumor cells and through anti-angiogenic ability to metastatic suppression during tumor development.

Purpose: This study aimed at investigating the effectiveness of Hsp90 inhibitor treatment in suppressing proliferation of cultured human retinal pigment epithelium (RPE) cells and elucidating its underlying mechanism.

Methods: Cultured RPE cells were treated with GA or 17-AAG and subjected for cell proliferation assay and cell cycle analysis. Expression of cell cycle and apoptotic regulators as well as survival signaling kinases, ERK1/2 and Akt, were monitored by Western blotting.

Results: it showed both GA and 17-AAG significantly inhibited RPE cell proliferation at micromolar levels. Treatment with both drugs resulted in growth arrests in G1 and S phases, an increase in sub-G1 population, upregulated expression of P53 and P21, as well as suppression of constitutive contents of phosphorylated ERK1/2 and total Akt proteins. Additionally, GA and 17-AAG significantly abrogated wortmannin-sensitized Akt phosphorylation.

Conclusions: GA and 17-AAG may modulate RPE cell proliferation and induce RPE cell apoptosis, possibly through p53-dependent pathway. They might potentially constitute a therapeutic agent for ocular disorders with RPE over proliferation, such as proliferative vitreoretinopathy.