Abstract
Benign prostatic hyperplasia (BPH) is a common disease that occurs mainly in older men. The pathogenesis of BPH is complex and patients face a prolonged treatment course, and novel drugs with better selectivity and lower toxicity are required. Incaspitolide A (compound TMJ-12) is a germacrane-type sesquiterpenoid compound extracted from the plant Carpesium carnuum. Extracts of C. carnuum are known to exert suppressive effects on BPH-1 cells. In the present study, we investigated the molecular mechanisms underlying the suppressive effect of TMJ-12 specifically on BPH-1 cells. A cytotoxicity assay indicated that TMJ-12 inhibited BPH-1 cell proliferation, while flow cytometry assays showed that TMJ-12 induced G2/M phase cell cycle arrest and the apoptosis of BPH-1 cells. TMJ-12 was also shown to regulate the expression of several apoptosis- and cell cycle-related proteins, namely Bcl-2, Bax, Bad, Caspase-9, Caspase-3, cyclin-dependent kinase 1 (CDK1), Cyclin B1, CDC25C, and c-Myc, among others. Collapse of the mitochondrial membrane potential (ΔΨm) following exposure to TMJ-12 was detected with the JC-1 staining assay. Further investigation revealed that treatment with TMJ-12 inhibited the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway by increasing the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Taken together, the results suggest that TMJ-12 prevents BPH-1 cell proliferation via the PI3K/AKT pathway by inducing apoptosis and cell cycle arrest.
Highlights
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate [1]
We investigated the effect of TMJ-12 on a benign prostatic hyperplasia cell line (BPH-1) and found that it induced apoptosis and cell cycle arrest by activating phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT) signaling
Our previous study found that TMJ-12, a germacrane sesquiterpenoid extracted from C. cernuum, inhibits the proliferation of the cervical cancer cell line, HeLa, and the liver cancer cell line, HepG2 [31]
Summary
Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate [1]. It is a common disease among older men, with up to 80% reported to have some degree of prostate enlargement by the age of 50 years [2]. The symptoms of BPH can be obstructive or irritative or may only affect the patient after micturition. Current treatments for BPH include surgery to resect the obstructive prostate tissue and minimize disease progression, or medications such as the 5-α reductase inhibitors, epristeride and finasteride, which block the conversion of testosterone into DHT, inhibiting prostatic hyperplasia, reducing prostate size, and slowing disease progression [3]. Since most BPH patients are elderly, most of them may have serious cardiovascular and cerebrovascular complications and cannot be treated with surgery [4].
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