Resistance to Paclitaxel Is Proportional to Cellular Total Antioxidant Capacity

Abstract

Paclitaxel, one of the most commonly prescribed chemotherapeutic agents, is active against a wide spectrum of human cancer. The mechanism of its cytotoxicity, however, remains controversial. Our results indicate that paclitaxel treatment increases levels of superoxide, hydrogen peroxide, nitric oxide (NO), oxidative DNA adducts, G 2 -M arrest, and cells with fragmented nuclei. Antioxidants pyruvate and selenium, the NO synthase inhibitor N W -nitro-L-arginine methyl ester, and the NO scavenger manganese (III) 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide all decreased paclitaxel-mediated DNA damage and sub-G 1 cells. In contrast, the glutamylcysteine synthase inhibitor buthionine sulfoximine (BSO) and the superoxide dismutase (SOD) inhibitor 2-methoxyestradiol (2-ME) increased the sub-G 1 fraction in paclitaxel-treated cells. These results suggest that reactive oxygen and nitrogen species are involved in paclitaxel cytotoxicity. This notion is further supported with the observation that concentrations of paclitaxel required to inhibit cell growth by 50% correlate with total antioxidant capacity. Moreover, agents such as arsenic trioxide (As 2 O 3 ), BSO, 2-ME, PD98059, U0126 [mitogen-activated protein/extracellular signal-regulated kinase inhibitors], and LY294002 (phosphatidylinositol 3-kinase/Akt inhibitor), all of which decrease clonogenic survival, also decrease the total antioxidant capacity of paclitaxel-treated cells, regardless whether they are paclitaxel sensitive or paclitaxel resistant. These results suggest that paclitaxel chemosensitivity may be predicted by taking total antioxidant capacity measurements from clinical tumor samples. This, in turn, may then improve treatment outcomes by selecting out potentially responsive patients. (Cancer Res 2005; 65(18): 8455-60)

Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses

“…CBS activity depends on the cellular redox state and is inhibited by NO or acidosis [46] and activated by ROS [45]. The balance between NO and ROS levels was shown as an important mechanism of the response to paclitaxel at low concentration [13,46]. In this study, at low dose of DTX, we found blockade of CBS as well as acidosis.…”

“…DTX was shown to interrupt the normal mitotic process through the disruption of microtubules [6], to have antiangiogenic effect [7], to activate several apoptotic cellular signals such as protein kinases and caspases [8,9], and to decrease structural and antioxidative gene expression [10,11]. Reactive oxygen and nitrogen species have been reported to be involved in taxane cytotoxicity [12,13], resulting from activation of NADPH oxidase [14]. Also DTX increased inducible nitric oxide synthase (iNOS) expression [15] and subsequent nitric oxide (NO) production [16] in breast cancer cells and through the stimulation of p38 activity in alveolar macrophages [17].…”

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

“…In addition, both classes of these drugs are able to generate ROS production in cancer cells, and ROS was found to be involved in DOX-and PTXinduced cell death in vitro and in vivo (Conklin, 2004;Ramanathan et al, 2005;Alexandre et al, 2006). Therefore, it was of interest to determine whether MnSOD could inhibit their ability to induce apoptosis.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…We also discovered that paclitaxel-induced cold allodynia was completely due to TRPA1 activation [103]. One final common pathway activated by the otherwise chemically heterogeneous group of molecules, such as chemotherapeutic agents, is the production of oxidative stress in different tissues and cells [147,148] and, through this effect they can potentially activate and/or sensitize the TRPA1 channel. Our recent works [103,146], however, indicated that oxaliplatin and paclitaxel do not directly gate TRPA1, as they do not cause any calcium response in primary culture of mouse or rat DRG neurons.…”