A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells.
Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel plant toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.
Butt
Alison J
AJ
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Vales 2010, Australia. abutt@garvan.org.au
Roberts
Caroline G
CG
Seawright
Alan A
AA
Oelrichs
Peter B
PB
Macleod
John K
JK
Liaw
Tracy Y E
TY
Kavallaris
Maria
M
Somers-Edgar
Tiffany J
TJ
Lehrbach
Gillian M
GM
Watts
Colin K
CK
Sutherland
Robert L
RL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007774:Lactation; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D027421:Persea / Q000737:chemistry*; D018515:Plant Leaves / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005233:Fatty Alcohols; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C098164:persin