TAT-Bim induces extensive apoptosis in cancer cells.
BACKGROUND
Suppression of apoptosis is central to the development of cancer and is associated with resistance to modern adjuvant treatments. Therefore, molecules and pathways of apoptotic processes are critical targets for the development of anti-cancer therapeutics. Since apoptosis is executed by intracellular proteins, molecular approaches must incorporate a method to deliver the treatment into the tumor cells.


METHODS
We utilized a peptide that contains two domains, a peptide transduction domain derived from the HIV-1 TAT protein and a biological effector domain, the BH3 domain from the pro-apoptotic Bcl-2 family member Bim. We examined whether this construct (TAT-Bim) induced apoptosis in several cancer cell lines (T-cell lymphoma (EL4), pancreatic cancer (Panc-02), and melanoma (B16)) and whether TAT-Bim treatment synergized with radiation. A mutant TAT-Bim peptide with no biologic activity (TAT-Bim-inactive) was used as a control. C57/BL6 mice were challenged with syngeneic cancer cell lines and the effects of intratumoral TAT-Bim injection on tumor growth and host survival were determined.


RESULTS
TAT-Bim was internalized by all cancer cells within two hours. TAT-Bim resulted in apoptosis in a dose dependent fashion in all cell lines and sublethal irradiation augmented the effects of TAT-Bim induced apoptosis. TAT-Bim significantly slowed tumor growth in murine models of pancreatic cancer and melanoma.


CONCLUSIONS
TAT-Bim exemplifies a strategy for cancer therapy that involves inducing apoptosis by antagonizing the endogenous anti-apoptotic machinery. Small peptide therapeutics, in combination with traditional adjuvant therapies such as radiation, may provide a valuable 'second hit' and drive tumor cells into programmed cell death.
Kashiwagi
Hiroyuki
H
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
McDunn
Jonathan E
JE
Goedegebuure
Peter S
PS
Gaffney
Mary C
MC
Chang
Katherine
K
Trinkaus
Kathryn
K
Piwnica-Worms
David
D
Hotchkiss
Richard S
RS
Hawkins
William G
WG
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D000072224:Bcl-2-Like Protein 11; D005260:Female; D015696:Gene Products, tat / Q000378:metabolism*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015696:Gene Products, tat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins