The immunosuppressive agents, like calcineurin inhibitors (CNI), are essential for the treatment of various inflammatory and autoimmune disorders, and also for the prevention of allograft rejection in transplant patients. However, the development, recurrence, and a rapid progression of cancer is a major problem in patients receiving immunosuppressive therapy. Kidney cancer is one of the most common cancers in CNI-treated patients, particularly in patients receiving solid organ transplants. The Ras-Raf pathway is often hyper- activated in renal cancer cells, particularly by the signaling through the epidermal growth factor receptor (EGFR). We have demonstrated that CNI treatment can directly activate the Ras-Raf oncogenic pathway to promote a rapid progression of renal cancer through the over-expression of the cytoprotective molecule heme oxygenase-1 (HO-1). The activated Ras-Raf-ERK pathway induces HO-1 through the transcription factor Nrf2; and HO-1 promotes the survival of renal cancer cells through the down-regulation of apoptosis and induction of angiogenesis. The apoptotic effects of rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were markedly enhanced upon HO-1 knockdown. Thus, it is critical to explore a mechanism(s) by which we can not only sustain immune suppression but also prevent cancer growth. Honokiol, a natural product originally isolated from Magnolia obovata, is a promising agent for mediating anti- inflammatory, anti-oxidant, pro-apoptotic and chemopreventive functions. In our preliminary studies, we have found that Honokiol can effectively down-regulate CNI-induced activation of the Ras-Raf pathway. We also demonstrate for the first time that Honokiol promotes apoptosis by inhibiting CNI-induced over-expression of HO-1, which plays a major role in Ras-mediated survival of renal cancer cells. Currently, there are very few agents to prevent cancer in patients undergoing immunosuppressive therapy; and most of these agents are associated with significant side effects and toxicities. Thus, it appears that Honokiol can have great potential to be used as a novel agent to prevent cancer growth in immunosuppressed patients. We hypothesize that Honokiol inhibits the cancer-promoting effects of CNI but retains its immunosuppressive functions for the prevention of immune disorders and allograft rejection. In our specific aims, we will study: 1) the mechanism(s) by which Honokiol can down-regulate CNI-induced and Ras-mediated activation of Nrf2-HO-1; and how Honokiol can prevent CNI-induced pathways for renal cancer growth and progression (Aim-1); and 2) the role of Honokiol in preventing CNI-induced and Ras-HO-1-mediated renal cancer growth after organ transplantation (Aim-2). Together, our studies should lead to a paradigm shift as the addition of Honokiol to CNI treatment can attenuate the Ras-Raf-induced cancer-promoting pathways of CNI, without affecting its required immunosuppressive functions.
Although the immunosuppressive agents, like calcineurin inhibitors (CNI), are essential for the treatment of various inflammatory disorders, and also for the prevention of allograft rejection, they promote cancer. Our findings should determine the effectiveness of a combination therapy using CNI and the natural product Honokiol as a strategy to prevent the development of renal cancer in immunosuppressed patients. It should lead to a paradigm shift as the addition of Honokiol to CNI treatment can attenuate the cancer-promoting pathways of CNI, without affecting its required immunosuppressive functions.
| Balan, Murugabaskar; Chakraborty, Samik; Flynn, Evelyn et al. (2017) Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth. Sci Rep 7:5900 |
