In the US, bladder cancer is the second most frequent genitourinary malignant tumor and is a fatal disease. Most human bladder cancers belong to the category of transitional cell carcinoma, which can further divide into invasive and non-invasive bladder cancer. T2 and higher stages of muscle-invasive bladder cancer have a poor prognosis and a high risk of metastasis.
Non-muscle-invasive bladder cancer is usually treating with transurethral resection of the bladder tumor; followed by close monitoring or Bacillus Calmette–Guérin (BCG) installation. However, the recurrence rate in patients with high-grade non-muscle-invasive bladder cancer after transurethral resection exceeds 75%; with a low survival rate. Since the recurrence rate of bladder cancer is still high, and many medications currently used for bladder cancer have strong side effects; the development of new drugs for bladder cancer treatment remains an important issue.
Marine soft corals are rich in biologically-active substances and have shown to exert anti-inflammatory, anti-fungal, antiviral, anti-cancer, and cytotoxic activities. Cembrane -type diterpene are common secondary metabolites of marine and terrestrial organisms; cytotoxicity is one of the major characteristics of compounds of this type. Previous studies have shown that compounds extracted from soft corals, such as diterpenes, diterpenoids; prostanoids can induce apoptosis in cancer cells, including colon cancer, oral squamous carcinoma, breast cancer, cervical cancer, hepatocellular carcinoma, bladder cancer, and melanoma cells.
The Bcl-2 family of proteins are regulators of apoptosis, and include distinct subfamilies; proapoptotic proteins with a multi-BH domain (such as Bax and Bak); proapoptotic proteins with a single BH3-only protein (such as Bad, Bim, and Bid), and antiapoptotic members such as Bcl-2 and Bcl-xl with all four BH domains conserved (such as Bcl-2, Bcl-xl, and Mcl-1).
Pathway in several organelles
Therefore studies have shown that intracellular stress may trigger the intrinsic apoptotic pathway in several organelles; mitochondria and the ER are two of the major organelles involved. In the presence of mitochondrial stress, Bax translocates to the outer membrane of the mitochondria and increases the membrane permeability; which causes alteration of the mitochondrial membrane potential, depolarization, and opening of mitochondrial pores.
In this study, they demonstrated that flaccidoxide-13-acetate induces apoptosis in RT4 and T24 bladder cancer cells; the process is mediated by induction of mitochondrial dysfunction and activation of ER stress; which also involves the initiation of the p38 and JNK pathways and inhibition of the PI3K/AKT pathway. The findings revealed that flaccidoxide-13-acetate-induced apoptosis in bladder cancer cells occurs via multiple pathways. Further study of the underlying mechanism is underway in our laboratory to identify specific targets of flaccidoxide-13-acetate in bladder cancer cells.