Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death.
Itraconazole is a common antifungal which may have promise for treating various human cancers. We report that itraconazole was cytotoxic to MCF-7 and SKBR-3 breast cancer cell lines via apoptosis by altering mitochondria membrane potential, reducing BCL-2 expression and elevating caspase-3 activity. Itraconazole also induced autophagic cell death via LC3-II expression upregulation, P62/SQSTM1 degradation, autophagosome formation and increases in autophagic puncta. Itraconazole treatment inhibited hedgehog pathway key molecular expression, such as SHH and Gli1, resulting in promotion of apoptosis and autophagy. The anti-proliferation effect of itraconazole-induced apoptosis and autophagy via hedgehog pathway inhibition was confirmed with Gli1 inhibitor GANT61 and SHH siRNA, GANT61 and SHH siRNA synergistically enhanced cytotoxicity induced by itraconazole. A human xenograft nude mouse model corroborated the anti-breast cancer activity as evidenced by reduced tumor size, and increased tumor tissue apoptosis and autophagy. Thus, itraconazole has a potent anti-breast cancer activity that may be improved when combined with hedgehog pathway inhibitors.
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China; College of Veterinary Medicine, Northwest A&F University, Yangling, China. Electronic address: 543596983@qq.com.
Xiaoya
X
Wang
Department of Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: Sanhuawei3@163.com.
Sanhua
S
Wei
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: zhaoyong8@aliyun.com.
Yong
Y
Zhao
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: changhong@fmmu.edu.cn.
Changhong
C
Shi
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: liupeij1989077@126.com.
Peijuan
P
Liu
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: zhangcaiqin-beibei@163.com.
Caiqin
C
Zhang
Department of Microbiology, Fourth Military Medical University, Xi'an, China. Electronic address: yflei@fmmu.edu.cn.
Yingfeng
Y
Lei
Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: zhangbo@fmmu.edu.cn.
Bo
B
Zhang
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: bone_1999@163.com.
Bing
B
Bai
College of Veterinary Medicine, Northwest A&F University, Yangling, China. Electronic address: Yonghuang@nwsuaf.edu.cn.
Yong
Y
Huang
Laboratory Animal Center, Fourth Military Medical University, Xi'an, China. Electronic address: hzhang@fmmu.edu.cn.
Hai
H
Zhang
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D061986:MCF-7 Cells; D008819:Mice, Nude; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C551027:GANT 61; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; C509239:SHH protein, human; D000071676:Zinc Finger Protein GLI1; D017964:Itraconazole
Apoptosis; Autophagic cell death; Breast cancer; Hedgehog pathway; Itraconazole