Experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE1-silencing RNA expression vector.
OBJECTIVE
Because of a developing resistance to chemotherapy agents, multiple myeloma (MM) has been an incurable disease until now. As a means to overcome MM tumor cell resistance and/or sensitize tumor cells to chemotherapeutic treatments currently used, we examined the role of human apurinic/apyrimidinic endonuclease 1 (APE1) in resistance and prognosis in patients with MM.


METHODS
Multiple myeloma cells were analyzed by using bone marrow specimens from 32 patients with MM and 10 normal volunteers.


RESULTS
The positive rate of APE1 protein expression was 65.6% in the bone marrow specimens of patients with MM with known clinical outcome. Positive rate of APE1 expression beyond grade 2 in the relapsed/refractory group was significantly higher than that in the untreated group. No positive results of grade > 2 were detected in bone marrow specimens from patients with noncancerous disease. It was also confirmed that the amount of APE1 protein in KM3 cells was positively correlated with the dose and action time of melphalan. Because APE1 was overexpressed in refractory/relapsed MM cells, siRNA-targeted technology was used to decrease APE1 levels in KM3 cells, with protein levels deceasing to 80%-90% within 24 hours and continuing to decease for 72 hours. The best dose and time of inhibiting expression of APE1 protein were 3 mug and 2 days long. A decrease in APE1 levels in siRNA-treated KM3 cells led to enhanced cell sensitization to melphalan.


CONCLUSIONS
The findings herein present prognostic and therapeutic implications for treating relapsed/refractory MM. The APE1-silencing RNA results demonstrate the feasibility of the therapeutic modulation of APE1 using a variety of molecules and approaches.
Yang
Zhen-Zhou
ZZ
Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, PR China.
Chen
Xing-Hua
XH
Wang
Dong
D
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008558:Melphalan / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D018613:Microscopy, Confocal; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051997:ADP-ribosyl Cyclase 1; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008558:Melphalan