Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

Abstract

Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a lethal cancer, cholangiocarcinoma (CCA), to natural killer (NK) cells. Treatment with cordycepin prior to and during co-culturing with NK-92 cells significantly increased cell death of KKU-213A as compared to solitary cordycepin or NK treatment. Moreover, sensitization activity was also observed in the combination of NK-92 cells and Cordyceps militaris extract that contained cordycepin as a major component. The cordycepin treatment remarkably caused an increase in TRAIL receptor (DR4 and DR5) expression in KKU-213A, suggesting the possible involvement of TRAIL signaling in KKU-213A sensitization to NK-92 cells. In conclusion, this is the first report on the sensitization activity of cordycepin on CCA cells to NK cytotoxicity, which supports that cordycepin can be further developed as an alternate immunomodulating agent.

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

“…CD56 expressing EVs in the circulation of CCA patients were enhanced compared to HVs, and not specifically changed by SIRT. There are ongoing approaches to apply NK cell stimulating substances in the therapy of CCA [ 51 ]. However, our current data do not reflect a significant relevance of SIRT as a potential stimulating factor of those cells or their enhanced communication via EVs in CCA patients.…”

Genistein Sensitizes Human Cholangiocarcinoma Cell Lines to Be Susceptible to Natural Killer Cells

“…Interestingly, this improvement of NK killing activity was found in perforin-deficient NK cells and could be inhibited by neutralizing antibodies to FasR and TRAIL-R, suggesting the NK cell-mediated cytotoxicity was promoted through TRAIL- and Fas-death receptor pathway [ 59 ]. Previous studies from our group, the increase of TRAIL-R after cordycepin treatment [ 22 ] and FasR after doxorubicin [ 21 ] associated with improvement of NK-92 cell killing activity in CCA and breast cancer, respectively, which emphasized the potential of FasR and TRAIL-R2 (DR5) modulation on NK cell killing activity. In this study, we demonstrated the effect of genistein on increasing either FasR or TRIAL-R expression in which the change of FasR expression was predominated in three cell lines over that of TRAIL-R ( Figure 6 ).…”

“…Recently, our group reported the immunosensitization effect of cordycepin, a bioactive compound of some Cordyceps spp. [ 22 ]. At a comparable concentration to genistein, cordycepin greatly increased the TRAIL-R expression and significantly improved the NK function to kill KKU213A but not KKU055 and KKU100 [ 22 ].…”

“…[ 22 ]. At a comparable concentration to genistein, cordycepin greatly increased the TRAIL-R expression and significantly improved the NK function to kill KKU213A but not KKU055 and KKU100 [ 22 ]. Since the effect of cordycepin was through TRAIL-R cascade whereas genistein was mainly through FasR, those suggested the possibility of the combination treatment to achieve the synergistic effect.…”

“…Chemotherapeutic drugs and natural compounds have been reported to be able to sensitize cancer cells by reversal of resistant cancer cells to be susceptible to cytotoxic immune cells [ 19 , 20 , 21 , 22 ]. Compared with traditional chemotherapies, natural compounds showed strong multitargeted anti-cancer effects and contain less side effects [ 23 ].…”