Chapter 4 Plant-derived alkaloid sinomenine potentiates steroid pharmacodynamics in
4.5 CONCLUSION
In this Chapter, I provided strong evidence that Japanese Boui-derived alkaloid SN potentiates the GC pharmacodynamics. However, the SN effects had no relation to the modification of P-glycoprotein mediated efflux function. I found that SN itself regulates the GR translocation in both Jurkat T cells and human activated PBMCs, and the combination of SN and MP showed stronger GR-modulatory activity. These effects of SN were suggested to be beneficial for treatment of RA patients, and thus GC combined with SN would be an alternative and reasonable therapeutic approach for RA.
GENERAL DISCUSSION AND CONCLUSION
T cells contribute to a wide spectrum of diseases such as T-cell acute lymphoblastic leukemia (T-ALL), autoimmune disorders, and organ transplant rejection [1], and GCs are substantially used for treatment of these patients [3]. However, lots of ALL patients show poor response to GC monotherapy [4]. High dose of GCs is also preferred for treatment of acute allograft rejection, while 30% of the patients receiving kidney transplantation show no or an inadequate response to GC which is an important risk factor for inferior renal allograft outcome [8]. Faced with these clinical challenges, it is urgent to develop more effective and less toxic therapy strategy for controlling diseases, which are implicated with T cell mediated diseases.
TET is a bisbenzylisoquinoline alkaloid derived from a medicinal plant Stephania tetrandra S. Moore (中国産防已). In Chapter 1, I examined the anti-T-ALL effects of TET and its analogue CEP, and the underlying mechanism by using a GC resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in Jurkat cells in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of apoptosis initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As important markers of apoptosis, p53 and Bax were both upregulated by treatment with TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will also be implicated as other possible mechanisms. During the process of apoptosis in Jurkat cells, JNK and p38 were activated by treatment with TET or CEP. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since
these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into clinical application of TET or CEP for the treatment of patients with relapsed T-ALL. Furthermore, the combination of GC and TET or CEP showed synergic inhibitory effect on Jurkat cell proliferation, indicating that TET or CEP possibly enhance GC pharmacodynamics and overcome GC resistance.
Because of the synergic effect of TET and MP observed in Chapter 1, I continued to investigate the immunosuppressive pharmacodynamics of the combination of TET and MP using PBMCs of healthy subjects in Chapter 2. TET decreased the IC50 value of MP significantly, but it showed little toxic effect on the Con A-activated PBMCs. Both TET and MP inhibited the secretion of pro-inflammatory cytokines TNFα and IL-6 and the combination showed stronger inhibitory ability. TET and/or MP did not increase the percentage of CD4+ CD25+Foxp3+ cells in CD4+ T cells. However, TET with or without MP significantly inhibited the function of drug efflux pump P-glycoprotein in CD4+ cells, CD8+ cells, and lymphocytes. TET tended to suppress the phosphorylation of MAPK and this effect was potentiated by MP. Meanwhile, TET dose-dependently enhanced the inhibitory effect of MP on MOLT-4/DNR T cells expressing high amount of P-glycoprotein on the cell membrane, with little effect on the parent MOLT-4 T cells. This difference might result from inhibition of P-glycoprotein efflux function by TET, which consequently increase GR translocation into nucleus. These TET effects were suggested to be beneficial for improving the immunosuppressive efficacy of GCs. Thus, GC combined with TET could be a new therapeutic approach to resolve GC-resistance possibly via inhibition of the P-glycoprotein function and blocking MAPK signaling pathway, but not affecting on Treg.
The synergic immunosuppressive effect of TET with MP was also examined in PBMCs of hemodialysis patients in Chapter 3, since these patients will be treated by GC after renal transplantation. TET potentiated the MP immunosuppressive pharmacodynamics to inhibit T cell mitogen-stimulated proliferation of PBMCs of hemodialysis patients in vitro.
According to these observations, it seems to be possible to combine MP and TET for
treatment of patients to reduce the MP therapeutic dose and thus decline its side effects. The pharmacological efficacy of TET and/or MP correlated with the CRP concentrations of the patients, whereas the efficacy did not correlate with other patient-related parameters including age, white blood cell counts, and serum creatinine concentrations.
The botanical sources of Boui are totally different between China and Japan. Chinese Pharmacopeia (2015 edition) lists the Radix Stephaniae Tetrandrae as Boui, while Caulis Sinomenii is collected as the herb of Boui in Japanese Pharmacopeia (17th edition). SN is the main active alkaloid of herbal plant Sinomenium acutum (Thunb.) (日本産防已). In Chapter 4, I also evaluated the potential additive effect of SN on GC pharmacodynamics in vitro to suppress the proliferation of human T cells. Although Japanese Boui-derived alkaloid SN also potentiated the GC pharmacodynamics like TET did, their action mechanisms seemed to be different. Unlike TET, the effect of SN had no relation to the P-glycoprotein mediated efflux function, since SN did not inhibit the P-glycoprotein function of PBMCs. As the underlying mechanism(s) of SN actions, I found that SN regulates the GR translocation in both Jurkat T cells and human PBMCs, and the combination of SN and MP showed stronger GR-modulatory activity.
In conclusion, my present study showed that TET and SN, isolated from Chinese Boui and Japanese Boui respectively, inhibit the proliferation of activated human T lymphocytes and potentiate GC pharmacodynamics by GR translocation modification via different signaling pathways. TET shows cytotoxic effect on GC resistant human leukemia Jurkat T cells by inducing apoptosis via multiple signaling pathways. TET combined with GC is also a possible candidate for treatment of patients with relapsed T-ALL.
ACKNOWLEDGMENTS
First and foremost, I want to thank my supervisors, Professor Haruki Yamada and Professor Toshihiko Hirano. They have taught me, both consciously and unconsciously, how good experiment is done. I appreciate all their contributions of time, ideas, and funding to make my Ph.D. experience productive and stimulating. I am also thankful for the excellent example they have provided as a successful pharmacist and professor. Their joy and enthusiasm on the research were contagious and motivational for me, even during tough times in the Ph.D. pursuit.
The other members in the Department of Clinical Pharmacology, Associate Professor Kentaro Sugiyama, Dr. Kenji Onda and Dr. Sachiko Tanaka, have contributed immensely to my personal and professional time at Tokyo University of Pharmacy and Life Science. The group has been source of friendships as well as good advice and collaboration. The past and present group members that I have had the pleasure to work with or alongside of are graduate and undergraduate students who have come to through laboratory.
In regard to the blood samples of healthy subjects and patients, I appreciate all the volunteers and the staffs from the Student Health Center and Keiyu Hosptial. Without their kind help, I would not finish my research successfully.
For this dissertation, I would like to thank my reading committee members: Professor Yoshihiro Mimaki, Professor Naohito Ohno and Professor Kunihiko Kitagaki for their time, interest, and helpful comments. I would also like to thank the other members of my oral defense committee for their time and insightful questions.
I gratefully acknowledge the funding sources that made my Ph.D. work possible. I was funded by Japan China Sasakawa Medical Fellowship for three years. My work was also partly supported by Hubei Provincial Hospital of Traditional Chinese Medicine.
Lastly, I would like to thank my friends and family members for their tremendous support.
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