Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumour necrosis factor-alpha in chemotherapy of multidrug-resistant hepatocellular carcinoma.
OBJECTIVE
Locoregional chemotherapy continues to be the mainstay for the treatment of unresectable hepatocellular carcinoma (HCC). One of the principal obstacles implicated in its unsuccessful therapy is multidrug resistance (MDR). Former studies have identified the multidrug-resistant nature and possible mechanisms of hepatoma cells both in vitro and in vivo. This work aimed to develop an effective strategy for the treatment of HCC with MDR.


METHODS
The treatment was exploited to inhibit the MDR cells by co-administration of the recombinant mutant human tumour necrosis factor-alpha (rmhTNF-alpha), a sublethal dose of chemicals [adriamycin (ADM), mitomycin and 5-FU] and hydroxyapatite nanoparticles (nHAPs). Real-time quantitative reverse transcriptase-polymerase chain reaction and electrochemiluminescence Western blot were used to detect the expression of several related genes.


RESULTS
The chemicals acted synergistically with rmhTNF-alpha and nHAP in suppressing the growth of hepatoma cells and inducing apoptosis of the cells, with the MDR phenotype reversed, as measured by intracellular ADM retention. Analysis of mRNA and protein revealed that rmhTNF-alpha inhibited the gene expression of XIAP, survivin, Ki67, PCNA, MDR1 and BCRP to some extent. Moreover, the inhibitory effects mentioned above could be as good or better than when nHAP is incorporated into the regimens.


CONCLUSIONS
rmhTNF-alpha was not only able to restore the chemotherapeutic sensitivity to HepG2/ADM, its xenograft model and clinical samples but also further inhibited the growth of these tumours by a combination of nHAP. These results strongly suggested that chemicals in combination with rmhTNF-alpha and nHAP may be beneficial for the local treatment of advanced HCC.
Department of Ultrasound, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Gaopeng
G
Li
Shengli
S
Dong
Junyuan
J
Qu
Zhengang
Z
Sun
Zhiyong
Z
Huang
Lu
L
Ye
Huifang
H
Liang
Xi
X
Ai
Wanguang
W
Zhang
Xiaoping
X
Chen
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D017886:Durapatite / Q000494:pharmacology*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000235:genetics; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011336:Probability; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D017886:Durapatite; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha