The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis

Veldhoen, Richard A.; Banman, Shanna L.; Hemmerling, D R; Odsen, R; Simmen, Thomas; Simmonds, Andrew; Underhill, D. Alan; Goping, Ing Swie

doi:10.1038/onc.2012.92

Cited by 102 publications

(96 citation statements)

References 37 publications

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“…Autophagy has also been implicated in the development of trastuzumab resistance in human epidermal growth factor receptor 2-positive breast cancer (30). A number of chemotherapeutic agents (anthracyclines and taxanes) are able to induce autophagy, and inhibition of autophagy increases drug toxicity via the induction of apoptosis in breast cancer cells (31,32).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Zhu

et al. 2015

Oncology Letters

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Abstract. Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer. IntroductionBreast cancer is the most frequently diagnosed cancer amongst females and the second most common cause of cancer-related mortality among women (1). One third of novel cancer diagnoses in females are breast cancer and a total of one in eight women will be diagnosed with breast cancer, with a lifetime risk of mortality due to breast cancer of 3.4% (1). Chemotherapy is one of the major systemic therapies available for the treatment of breast cancer. A recent meta-analysis of the outcome of 100,000 patients with breast cancer, confirmed the benefit of cyclophosphamide-, methotrexate-and fluorouracil-therapies and anthracycline-based therapies with absolute reduction of mortalities of 6.2 and 6.5%, respectively, at 10 years (2). Despite progress in the improvement of chemotherapeutic strategies, the ability to treat advanced breast cancer remains poor, mainly due to the chemoresistance of cancer cells to standard chemotherapy. Numerous anti-apoptotic and cytoprotective pathways have been associated with the chemoresistance of cancer cells (3,4).Heme oxygenase (HMOX) is a microsomal enzyme, which catalyzes the initial, rate-limiting step in the degradation of heme, and has a crucial role in the recycling of iron (5). The enzymatic activity of HMOX also produces CO, ferrous iron and biliverdin. Thus, HMOX is able to reduce oxidative stress, attenuate inflammatory responses and lower the rate of apoptosis (6). HMOX-1, an isoform of HMOX, may be induced in response to cellular stress and diverse oxidative stimuli (7). HMOX-1 is frequently overexpressed in a range of cancers, including hepatoma, prostate cancer, melanoma and brain tumors (8-11). HMOX-1 promotes proliferation in human melanoma and pancreatic cancer cell lines (10,12). As HMOX-1 is a potent inducer of vascular endothelial growth factor (VEGF), a crucial factor involved in tumor angiogenesis, it has also been recognized to stimulate angiogenesis and thus support tumor progression (13). Additionally, overexpression of...

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Section: Discussionmentioning

confidence: 99%

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Zhu

et al. 2015

Oncology Letters

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Section: Figurementioning

confidence: 99%

“…A distinct mechanism dependent on cell cycle stage was recently described. In non-mitotic paclitaxeltreated cells, the formation of autophagosomes was effective but their movement and maturation was inhibited (Veldhoen et al, 2013).In the case of CMA, although chemical activators of this pathway are currently available (Anguiano et al, 2013), considerably less progress has been made in the identification of specific inhibitors. Particularly, some low MW compounds described earlier as specific CMA modulators have since been shown to exhibit other activities, which somewhat diminishes their initial interest (Finn et al, 2005;Cuervo and Wong, 2014).…”

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confidence: 99%

Pharmacological regulators of autophagy and their link with modulators of lupus disease

Gros

Muller

2014

British J Pharmacology

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Autophagy is a central regulator of cell survival. It displays both anti-and pro-death roles that are decisive in the maintenance of cell homeostasis. Initially described in several eukaryotic cellular models as being induced under nutrient stress favouring survival by energy supply, autophagy was found later to display other decisive physiological roles, especially in the immune system. Thus, it is involved in antigen presentation and lymphocyte differentiation as well as in the balance regulating survival/death and activation of lymphocytes. Autophagy therefore appears to be central in the regulation of inflammation. The observation that autophagy is deregulated in systemic lupus erythematosus is recent. This discovery revives the programme dealing with the design and development of pharmacological autophagy regulators in the therapeutic context of lupus, a debilitating autoimmune disease that affects several million people in the world. A large number of molecules that positively and negatively regulate autophagy have been described, most of them with therapeutic indications in cancer and infection. Only a few, however, are effectively potent activators or inhibitors endowed with experimentally demonstrated selective properties. In this review article, we highlight the most relevant ones and summarize what we know regarding their mechanism of action. We emphasize the link between pharmacological regulators of autophagy and inducers or inhibitors of lupus disease and discuss the fundamental and pharmacological/therapeutic interest of this functional interplay. AbbreviationsCMA, chaperone-mediated autophagy; CQ/HCQ, chloroquine/hydroxychloroquine; HSPA8/HSC70, heat shock cognate protein of 70 kDa; LAP, LC3-associated phagocytosis; LC3, microtubule-associated protein light chain 3; MHC-I/II, MHC class I or MHC class II; mTOR, mammalian target of rapamycin; PRR, pattern recognition receptors; SLE, systemic lupus erythematosus TLR 9 RapamycinThis Table lists the protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and the Concise Guide to PHARMACOLOGY 2013/14 (Alexander et al., 2013a). Autophagy and its implication in human diseasesAutophagy is a catabolic process related to lysosomal degradation. Opposed to heterophagy, which implies degradation of substrates from outside the cell, autophagy catabolizes the cytoplasmic content. There are three main pathways involved in autophagy. The first one, called microautophagy, involves the direct engulfment of cytosolic material into the lysosome. Its core molecular machinery and regulation as well as its possible implication in human diseases are still poorly understood. In this review, we will focus the first part of our comments on the two other types of autophagy, namely, macroautophagy and chaperone-mediated autophagy (CMA). Historically, the term 'autophagy' was proposed by Christian De Duve in the ...

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“…In mitotic cells, paclitaxel blocks the activation of the VPS34 complex by inducing inhibitory phosphorylation of VPS34 at T159, which is mediated by mitotic kinases such as CDK1 (68). In non-mitotic cells, paclitaxel inhibits autophagosome trafficking to block maturation of autophagic vesicles (69). The ability of microtubule targeting agents to negatively regulate autophagy suggests that their efficacy as anticancer therapeutics may be partially attributable to their ability to inhibit autophagy.…”

Section: R E V I E W S E R I E S : a U T O P H A G Y 9 Jciorgmentioning

confidence: 99%

Pharmacologic agents targeting autophagy

Vakifahmetoglu-Norberg¹,

Xia²,

Yuan³

2015

J. Clin. Invest.

210

177

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The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis

Cited by 102 publications

References 37 publications

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Pharmacological regulators of autophagy and their link with modulators of lupus disease

Pharmacologic agents targeting autophagy

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