Improved therapeutic efficacy against murine carcinoma by combining honokiol with gene therapy of PNAS-4, a novel pro-apoptotic gene.
PNAS-4, a novel pro-apoptotic gene activated during the early response to DNA damage, can inhibit proliferation via apoptosis when overexpressed in some tumor cells. Recent studies have indicated that honokiol can induce apoptosis, inhibit angiogenesis, and suppress tumor growth. In the present study, we investigated whether mouse PNAS-4 (mPNAS-4) could augment the apoptosis of tumor cells induced by honokiol in vitro, and whether the antiangiogenic activity of honokiol and induction of apoptosis by mPNAS-4 could work cooperatively to improve the antitumor efficacy in vivo. In vitro, mPNAS-4 inhibited proliferation of murine colorectal carcinoma CT26 and Lewis lung carcinoma LL2 cells through induction of apoptosis, and significantly augmented the apoptosis of CT26 and LL2 cells induced by honokiol. Compared with treatment with mPNAS-4 or honokiol alone, in vivo systemic administration of an expression plasmid encoding mPNAS-4 and low-dose honokiol significantly suppressed tumor growth through the enhanced induction of apoptosis and the augmented inhibition of angiogenesis. Our data suggest that the combined treatment with mPNAS-4 plus honokiol augments antitumor effects in vitro and in vivo, and that the improved antitumor activity in vivo may be associated with enhanced induction of apoptosis and augmented inhibition of angiogenesis. The present study may provide a novel and effective method for the treatment of cancer.
Yuan
Zhu
Z
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Liu
Huanyi
H
Yan
Fei
F
Wang
Yongsheng
Y
Gou
Lantu
L
Nie
Chunlai
C
Ding
Zhenyu
Z
Lai
Songtao
S
Zhao
Yuwei
Y
Zhao
Xinyu
X
Li
Jiong
J
Deng
Hongxin
H
Mao
Yongqiu
Y
Chen
Lijuan
L
Wei
Yuquan
Y
Zhao
Xia
X
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D020287:In Situ Nick-End Labeling; D017705:Lignans / Q000627:therapeutic use*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D000498:Allyl Compounds; D010636:Phenols
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D017705:Lignans; D008081:Liposomes; D019001:Nitric Oxide Synthase; C541601:PNAS4 protein, mouse; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols