Abstract
A clerodane diterpene compound 16-hydroxycleroda-3,13-dien-15,16-olide (CD) is considered a therapeutic agent with pharmacological activities. The present study investigated the mechanisms of CD-induced apoptosis in T24 human bladder cancer cells. CD inhibited cell proliferation in a concentration and time-dependent manner. CD-induced overproduction of reactive oxygen species and reduced mitochondrial membrane potential, associated with reduced expression of Bcl-2 and increased levels of cytosolic cytochrome c, cleaved PARP-1 and caspase-3. In addition, CD treatment led to cell cycle arrest at the G0/G1 phase and inhibited expression of cyclin D1 and cyclin-dependent kinases 2 and 4 and led to increased levels of p21, p27Kip1 and p53. All of these events were accompanied with a reduction of pEGFR, pMEK1/2, pERK1/2, pAkt, pmTOR, pP70S6K1, HIF-1α, c-Myc and VEGF. RNAseq-based analysis revealed that CD-induced cell death was characterised by an increased expression of stress and apoptotic-related genes as well as inhibition of the cell cycle-related genes. In summary, CD induces apoptosis in T24 bladder cancer cells through targeting multiple intracellular signaling pathways as a result of oxidative stress and cell cycle arrest.
Highlights
Phase-contrast microscopy revealed that treatment with CD caused cell shrinkage and led to the formation of apoptotic vacuoles (Figure 1A)
CD treatment inhibited B-cell lymphoma 2 (Bcl-2) antiexpression. These results suggest that CD induces mitochondrial-dependent apoptosis in bladder cancer (BC) cells apoptotic protein expression
We demonstrate that a clerodane diterpene compound isolated from P. longifolia
Summary
16-hydroxycleroda-3, 13-dien- 16, 15-olide (CD) is one of the major active compounds of clerodane diterpenes and has been found to exhibit numerous pharmacological functions, such as anti-lipogenic [1], anti-leishmanial [2], anti-fungal [3], anti-inflammation [4], and anti-cancer activities [5]. CD has been tested in several cancer cell lines and presents anti-tumour and anti-cancer activities [5,7,8]. The anti-tumour effects of CD on human bladder cancer (BC) cells remain unknown. BC, known as bladder urothelial carcinoma, is the most common malignancy of the genitourinary tract, with an incidence rate of 350,000–380,000 cases reported per year worldwide, and accounts for 2–3% of the worldwide cancer burden [9]. Overexpression of epidermal growth factor receptor (EGFR) is common in solid tumours, including breast, lung, prostate, and bladder cancer [14]. The present study aims to determine the mechanisms of CD-induced cell death in the T24 human BC cell line by assessing apoptotic signals, cell cycle distribution, and EGFR-related signalling pathways
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