Specific RSK Kinase Inhibition by Dibenzyl Trisulfide and Implication for Therapeutic Treatment of Cancer

Jamaican Guinea Hen weed
Petiveria alliacea
dibenzyl trisulfide
kinase inhibitor
RSK
cancer

Cancer is the leading cause of death by disease in Jamaica, with an life-time risk of 1 in 4 for males and 1 in 6 for females; prostate and breast being the most prevalent and deadly (1). The lack of proper screening methods and treatment facilities poses a major hindrance in the effort to reduce this cancer epidemic. Jamaica is known for its rich biodiversity and usage of medicinal plants for treating ailments of all kinds, and major efforts are underway to blend tradition with modern biomedical science. Approximately 40% of medications prescribed and used today are largely composed of compounds derived from medicinal plants. The sub-tropical shrub, Petiveria alliacea L., commonly known in Jamaica as the “Guinea Hen Weed”, has certain medicinal value. It is traditionally used in folk medicine to enhance memory and in the treatment of the common cold, flu, other viral or bacterial infections, inflammation, diabetes, and cancer.

Có thể bạn quan tâm

Isolation of the immunomodulatory compound, dibenzyl trisulfide (DTS) (Figure 1) (2), and closer investigation of its biological activity, revealed its involvement in the mitogen-activated protein kinase (MAPK) signal transduction pathway (3). The MAPK pathway orchestrates a series of phosphorylation events essential for the proper regulation of embryogenesis, cell differentiation, cell proliferation, and cell death (4). Dysregulation of the pathway has been implicated in the pathogenesis of several human degenerative diseases and a variety of cancers (5). In neuroblastoma cells and human lung fibroblasts, DTS causes disassembly of microtubules, resulting in an anti-mitotic effect and subsequent inhibition of cell proliferation (3). The anti-proliferative and/or cytotoxic effects of DTS on several human cancer cell lines (SH-SY5Y neuroblastoma, MCF7 and M231 breast, IPC melanoma, A549 small cell lung cancer, A637 primary bladder carcinoma, Jurkat leukemia, A2780 and OVCAR4 ovarian, HT1080 fibrosarcoma, H460 non-small cell lung cancer, HeLa adenocarcinoma, and TE-671 sarcoma) have been presented (6).

Bạn đang xem: Specific RSK Kinase Inhibition by Dibenzyl Trisulfide and Implication for Therapeutic Treatment of Cancer

Xem thêm : Completely Random Product Reviews

It is estimated that approximately 30% of pharmaceutical industry research currently focuses on the study of kinases and their regulation, foreseeing a strong potential for therapeutic benefit (7). The feasibility of targeting protein kinases in cancer therapy with examples of inhibitors in clinical use are discussed in a review article by Pearson and Fabbro (8). Emerging roles for the RSK (p90 ribosomal s6 kinase) family of serine/threonine protein kinases, the most downstream effectors of the MAPK/ERK (Ras-extracellular signal regulated kinase) pathway, have recently been reported (9). Of particular interest to our research group, is the pro-survival role of RSK in cancer. RSKs promote tumorigenesis in a variety of hormone-dependent and -independent cancers and its specific inhibition represents a promising therapeutic strategy (10).

Estrogen receptor-α (ERα) is a known target of RSK (11) and elevated levels of RSK are observed in various cancers (12, 13). Inhibition of RSK using the botanically-derived compound, SL0101, prevents breast cancer cell proliferation (14) and attenuates prostate cancer cell growth (13). Although RSK2 is most closely linked to human cancers (15), other isoforms also demonstrate anticancer activity. High protein expression of RSK3 and RSK4 in breast cancer cells confers resistance to apoptosis induced by PI3K/mTOR pathway inhibitors; however, resistance is overcome by combining PI3K/mTOR inhibitors and MEK (MAP/ERK) kinase inhibitor or pan-RSK kinase inhibitor (12). Surprisingly, MEK 1/2 inhibitors are still largely being used to study the physiological role of RSK (16). Unfortunately, therapeutic targeting of upstream components or “global regulators” of the MAP/ERK signaling pathway (i.e. MEK and Raf) causes significant patient side-effects and has so far been unsuccessful in the clinic (17). Therefore, more selective RSK inhibitors are required to study the specific function of RSK proteins. To date, there are only 3 inhibitors used to study the physiological function of RSKs however, there are no RSK isoform-specific inhibitors. Here we report, the isoform-specific inhibitory effect of DTS on the C-terminal kinase domain (CTKD) of RSK-1.