Effective Evaluation Of TRAIL Combined With Chemotherapeutic Drug Treating Hematologic Neoplasms In Vitro

Background: Hematologic neoplasms are a group of diseases with highly malignant clones of hematopoietic stem/progenitor cells,which has high morbidity and mortality rates.Currently,chemotherapeutic drugs used to treat hematologic neoplasms can’t effectively target tumor cells,causing significant toxic side effects in vivo.Tumor necrosis factor-related apoptosis inducing ligand（TRAIL）is capable of binding to death receptors highly expressed on the surface of tumor cells,exerting excellently anti-tumor effects via triggering apoptosis cascade reactions,binding to decoy receptors highly expressed on the surface of normal cells,shielding normal cells from the attack of TRAIL by blocking the conduction of related apoptotic signals.Due to the unique target killing advantage,TRAIL has become a promising anti-hematological neoplasm candidate.However,the inherent resistance of some hematologic neoplasms to TRAIL limits its extensively use.Objective: To explore whether hematologic neoplasms express TRAIL receptors and their sensitivity to TRAIL.For TRAIL resistant hematologic neoplasms,whether TRAIL combined with low-dose chemotherapeutic drug could enhance the antihematological neoplasm effect of TRAIL.Methods and results: First,we analyzed TRAIL receptors expression in hematologic neoplasm patients and hematologic neoplasm cell lines by flow cytometry.The results showed that the four types of hematologic neoplasms,including acute myeloid leukemia（AML）,B-cell acute lymphoblastic leukemia（B-ALL）,B-cell chronic lymphatic leukemia（B-CLL）and multiple myeloma（MM）all expressed death receptors at high level（positive rate≥ 50%）,and low or no expressed decoy receptors（positive rate ≤10%）,confirming the ability of TRAIL to effectively express death receptors,which is also a prerequisite for TRAIL to exert the antitumor effect.Subsequently,we successfully produced the soluble recombinant protein TRAIL in virtue of molecular cloning and protein expression techniques,and further validated its physicochemical properties.Next,we evaluated the anti-tumor effects of TRAIL to hematologic neoplasms,the results showed that the IC50 of TRAIL against four AML cell lines（MOLM-13,HL60,U937 and THP-1）and two ALL cell lines（Ramous and Raji）were at the nanomolar level,but the sensitivity of TRAIL varied among these six cell lines.For the four resistant cell lines（U937,THP-1,Ramous and Raji）,we combined TRAIL with typical chemotherapeutic drugs with low dose,such as bortezomib,disulfiram and idamycin to enhance the antitumor effect of TRAIL.These results indicated that the combination of TRAIL with bortezomib showed a synergistic effect in U937,THP-1 and Raji;the combination of TRAIL with disulfiram exerted a synergistic anti-tumor effect in U937 and THP-1;while the combination of TRAIL with idamycin only enhanced the killing effect of TRAIL in THP-1.In general,the strategy of TRAIL combined with chemotherapeutic drugs in our study provides a novel idea for efficient and low-toxicity targeted therapy for hematologic neoplasms.Conclusion: TRAIL combined with bortezomib,disulfiram and showed idamycin respectively,great heterogeneity among different cell lines,but also enhanced the antihematologic neoplasms effect of TRAIL at various levels.This combination therapy strategy in our study provides a novel idea for efficient and low-toxicity targeted therapy for hematologic neoplasms.