p53-independent apoptosis induced by paclitaxel through an indirect mechanism

Abstract

The efficacy of chemotherapeutic agents may be determined by a number of different factors, including the genotype of the tumor cell. The p53 tumor suppressor gene frequently is mutated in human tumors, and this may contribute to chemotherapeutic resistance. We tested the requirement for wild-type p53 in the response of tumor cells to treatment with paclitaxel (trade name Taxol), an antineoplastic agent that stabilizes cellular microtubules. Although paclitaxel is broadly effective against human tumor xenografts in mice, including some known to carry p53 mutations, we found that p53-containing mouse tumor cells were significantly more sensitive to direct treatment with this drug than were p53-deficient tumor cells. In an attempt to reconcile this apparent discrepancy, we examined the requirement for p53 in the cytotoxic effects of tumor necrosis factor ␣ (TNF-␣), a cytokine released from murine macrophages upon paclitaxel treatment. Conditioned medium from paclitaxel-treated macrophages was capable of inducing p53-independent apoptosis when applied to transformed mouse embryonic fibroblasts and was inhibitable by antibodies against TNF-␣. Furthermore, in response to direct treatment with TNF-␣, both wild-type and p53-deficient tumor cells underwent apoptosis to similar extents and with similar kinetics. Our results suggest that the efficacy of paclitaxel in vivo may be due not only to its microtubule-stabilizing activity, but its ability to activate local release of an apoptosis-inducing cytokine.

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

“…Results of this study demonstrated that paclitaxel in this range of concentrations activated IL-6 through the activation of JNK signaling pathway but not through the LPS-like activity of paclitaxel. First, the 1 mM concentration of paclitaxel used in this study was much lower than that reportedly (3-140 mM) effective for upregulation of IL1alpha, IL-1 beta, IL-8 and TNF-alpha (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997;Kawasaki et al, 2000Kawasaki et al, , 2003Perera et al, 2001;Takeda et al, 2003). Second, no upregulation of TLR4, MyD88, or NF-IL6 in terms of mRNA levels in BR cells treated with 1 mM paclitaxel was noted (Figure 6a).…”

“…At high concentrations (5-30 mM), paclitaxel has been reported to exert endotoxin LPS-like effects through treatment on macrophage-like cells, including the upregulation of various cytokines (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997). Lipopolysaccharidelike effects of paclitaxel were thought to be conveyed through TNF receptor (Ding et al, 1990) or TLR-4 (Kawasaki et al, 2000(Kawasaki et al, , 2003Perera et al, 2001).…”

“…Treatment of macrophage-like cells with high concentrations (5-30 mM) of paclitaxel has been reported to exert endotoxin lipopolysaccharide (LPS)-like effects, including the upregulation of various cytokines (Ding et al, 1990;Lee et al, 1996;Lanni et al, 1997). More recently, Toll-like receptor 4 (TLR4) on murine macrophage has been shown to be the receptor for paclitaxel (Kawasaki et al, 2000(Kawasaki et al, , 2003Perera et al, 2001).…”

Paclitaxel-induced cell death

“…55 Despite its unlikely clinical relevance due to the suprapharmacologic concentration of paclitaxel required, this observation still strengthens the notion that paclitaxel has multiple effects on the cell. Paclitaxel is also shown to activate interleukin (IL)-8 transcriptionally in ovarian carcinoma cells, 90 and the transcription factor (AP-1, NF-B) binding sites of the IL-8 promoter are required for activation by paclitaxel.…”

Cytoskeleton and paclitaxel sensitivity in breast cancer: The role of β‐tubulins

“…Also data concerning p53 alterations have been reported 47,48 but with contradictory conclusions explained as due to the differences in laboratory assays utilised and characteristics of clinical series considered.…”