The Effect of 5-Aminolevulinic Acid and Its Derivatives on Protoporphyrin IX Accumulation and Apoptotic Cell Death in Castrate-resistant Prostate Cancer Cells

Abstract

Objective To examine whether pharmacologically relevant zinc-binding agents are capable of depleting XIAP in tumor cells. Our prior work reveals that treatment with zinc chelating agents induces selective down-regulation of the X-linked inhibitor of apoptosis protein (XIAP) in cancer cells of various origins. A precursor of the heme synthetic pathway, 5-aminolevulinic acid (5-ALA), is metabolized to protoporphyrin IX (PPIX), which is highly reactive with zinc. We assessed whether modified versions of 5-ALA with lipophilic side chains can enhance efficacy and selectivity with respect to PPIX accumulation, XIAP depletion, and TNF-related apoptosis-inducing ligand (TRAIL) – mediated apoptosis in human castration resistant prostate cancer (CRPC) cells. Methods Seven modified versions of 5-ALA (five esters and two amides) were synthesized. Levels of endogenous PPIX were examined by flow cytometry. XIAP expression was examined by Western blotting. TUNEL assay was used to assess cell apoptosis. Results were compared qualitatively. Results Accumulation of endogenous PPIX by CRPC cells was shown to be directly related to the carbon chain length of the esterified 5-ALA derivatives. In fact, treatment with ALA-HE was superior to that achieved by 5-ALA with respect to XIAP down-regulation. 5-ALA and ALA-HE in combination with TRAIL significantly enhanced apoptotic cell death in CRPC cell lines. Conclusion Esterified derivatives of 5-ALA alone or in combination with other agents may provide therapeutic opportunities in treatment of CRPC by harnessing apoptotic pathways that are triggered by cellular zinc imbalance.

Immobilization of ALA‐ZnII Coordination Polymer Pro‐photosensitizers on Magnetite Colloidal Supraparticles for Target Photodynamic Therapy of Bladder Cancer

“…In conjunction with the results in Table , Fe 3 O 4 @ALA‐Zn II and ALA showed a dose‐dependent and time‐dependent inhibiting of XIAP (Figure a). A critical comparison could find that Fe 3 O 4 @ALA‐Zn II induced slightly more XIAP depletion in T24 cells compared with ALA (Figure b), possibly because the Zn ions are associated with ALA‐induced PpIX and thus enhance the depletion of XIAP …”

Antitumor Effects of 5-Aminolevulinic Acid on Human Malignant Glioblastoma Cells

“…Apoptosis is a key mechanism for the maintenance of cell proliferation and cell death in GBM [ 29 ], and targeting apoptosis represents an optimal therapeutic strategy for GBM [ 30 ]. Studies have shown that 5-ALA increases apoptotic cell death in resistant prostate cancer cells [ 31 ] and enhancement of intracellular PP-IX induces p53-dependent apoptosis in lymphocytic leukemia cells [ 32 ]. A reduction in cell viability following the application of 5-ALA and photodynamic therapy has been attributed to cell apoptosis via the increasing p53 protein level as well as Bax/Bcl-2 ratio [ 33 , 34 ].…”

Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo

“…Androgen-independent human PC-3 prostate cancer cells (Teper et al, 2012) were obtained from ATCC (Rockville, MD). Cells were cultured in RPMI 1640 (Bio-Whittaker, Walkersville, MD) supplemented with 10% FBS (Hyclone, Logan, UT), penicillin (100 μ/ml), streptomycin (100 μg/ml), sodium pyruvate (1 mM) and non-essential amino acids (0.1 mM) under conditions indicated in the figure legends.…”