title: Activated calphostin C cytotoxicity is independent of p53 status and in vivo metastatic potential.
abstract: The development of novel therapeutic agents to modulate programmed cell death independent of genetic background or malignant potential is a primary goal of modern cancer therapy. In this report, the light activation- and concentration-dependent cytotoxicity of calphostin C, a photoactivatable perylenequinone, is carefully evaluated using a series of nine well-characterized human and rodent prostate cancer cell lines representing the spectrum of disease progression (e.g., variations in metastatic ability, ploidy, and tumor suppressor gene status). Treatment of these cancer cell lines with nanomolar concentrations of calphostin C in combination with increasing amounts of light exposure established a relationship between light and dose dependence of calphostin C cytotoxicity. The induction of apoptosis is rapid, as evidenced by the fact that immediately after treatment, cells exposed to calphostin C with light activation exhibit both morphological and biochemical changes consistent with apoptosis (cellular and nuclear shrinkage and chromatin condensation). For example, 78% of cells treated with 100 nM calphostin C in combination with 2 h of light activation underwent apoptosis within 24 h of treatment. DNA ladder formation could be detected within 12 h of treatment. In the absence of light activation, treatment with calphostin C at all concentrations tested had no acute or durable cytotoxic effects in any of the cell lines. Our findings demonstrate that calphostin C cytotoxicity is strictly light dependent. Furthermore, its efficacy is independent of the genetic background, p53 status, or in vivo malignant potential of a cell, making it a suitable candidate for the treatment of heterogeneous tumor cell populations.
authors.affiliation: Section of Urology, University of Chicago, Illinois 60637, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Dubauskas
authors.forename: T P
authors.initials: TP
authors.lastname: Beck
authors.forename: S J
authors.initials: SJ
authors.lastname: Chmura
authors.forename: D A
authors.initials: DA
authors.lastname: Kovar
authors.forename: M M
authors.initials: MM
authors.lastname: Kadkhodaian
authors.forename: M
authors.initials: M
authors.lastname: Shrivastav
authors.forename: T
authors.initials: T
authors.lastname: Chung
authors.forename: W M
authors.initials: WM
authors.lastname: Stadler
authors.forename: C W
authors.initials: CW
authors.lastname: Rinker-Schaeffer
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001711:Biotransformation; D006801:Humans; D008027:Light; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D051381:Rats; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
chemical_list: D000903:Antibiotics, Antineoplastic; D009281:Naphthalenes; D016159:Tumor Suppressor Protein p53; C058819:calphostin C