Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

Sarkaria, Jann N.; Kitange, Gaspar J.; James, C. David; Plummer, Ruth; Calvert, Hilary; Weller, Michael; Wick, Wolfgang

doi:10.1158/1078-0432.ccr-07-1719

Cited by 316 publications

(290 citation statements)

References 59 publications

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“…19 Therefore, we wondered whether the FXN level of glioma cells might modulate apoptosis sensitivity and cytotoxic effects of alkylating agents currently used for glioma therapy. First, we tested the sensitivity toward staurosporine, a wellknown trigger of intrinsic apoptosis.…”

Section: Frataxin Enhances Sensitivity To Intrinsic Apoptosismentioning

confidence: 99%

Dual role of the mitochondrial protein frataxin in astrocytic tumors

Kirches

Andrae

Hoefer

et al. 2011

Laboratory Investigation

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The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H 2 O 2 or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.

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Section: Frataxin Enhances Sensitivity To Intrinsic Apoptosismentioning

confidence: 99%

Dual role of the mitochondrial protein frataxin in astrocytic tumors

Kirches

Andrae

Hoefer

et al. 2011

Laboratory Investigation

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“…This compound was also able to induce apoptosis in human colon cancer cells through activation of caspase-3 and -9 (9). In the present study we have investigated the ability of ISP in inducing apoptosis in vitro in two types of apoptosis-resistant cancers, i.e., glioblastoma (GBM) (10)(11)(12) and non-small cell lung cancer (NSCLC) (13,14). We used as a positive control the human PC-3 prostate cancer cell line in which plantderived compounds, such as narciclasine (15) or sodium pump inhibitors (16) are able to induce apoptosis in vitro.…”

Section: Introductionmentioning

confidence: 99%

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

Baldé

Mégalizzi²,

Cao³

et al. 2010

Int J Oncol

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Abstract. Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, an East African small tree. We have reported previously pro-apoptotic effects induced in vitro by ISP in the human HCT-116 colon cancer cell line, a model that displays relative sensitivity to apoptosis. In the present study, we observed that the in vitro growth inhibitory activities of ISP are similar in cancer cells that display sensitivity versus resistance to apoptosis. We made use of the U373 glioblastoma and the A549 non-small cell lung cancer (NSCLC) cell lines as models relatively resistant to apoptosis, and the human PC-3 prostate cancer cell line as a model relatively sensitive to apoptosis. While ISP induced transient decreases in [ATP] i and apoptosis in human U373 GBM cells, it did not provoke such features in A549 NSCLC cells. It thus seems that ISPinduced anti-cancer activity can lead to pro-apoptotic effects as a consequence, while apoptosis seems not to be the main cause by which ISP induces cancer cell death. ISP is a compound that merits further investigations in order to: i) identify the mechanism(s) of action by which it kills cancer cells, and ii) hemisynthesize novel ISP derivatives aiming to overcome, at least partly, the resistance of metastatic cancers to apoptosis. IntroductionDespite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors (1). Indeed, in the common advanced cancers, over 40 years of cytotoxic drug development has brought no significant change in cure rates (1). Savage and colleagues (1) report that one interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. These authors thus suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells (1). In fact, >90% of cancer patients die from their metastases (2). Drug resistance, either acquired or intrinsic, often prevents tumor cells from undergoing sufficient levels of apoptosis, resulting in cancer cell survival and treatment failure (1,2). The metastatic process is inherent to a significant level of resistance to apoptosis. Indeed, as a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighboring cells (3). This cell death process has been termed 'anoikis' (3). Tumor cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems (3). Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to anoïkis (3).Plants have played a dominant role in the development of sophisticate...

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“…Although TMZ is the drug of choice in the treatment of GBM patients, frequent treatment failures result in resistance to this drug and fatal GBM recurrences (Furnari et al ., 2007; Sarkaria et al ., 2008). Major DNA adducts generated by TMZ are N 7 ‐methylguanine (N 7 ‐MeG; 60‐80%), N 3 ‐methyladenine (N 3 ‐MeA; 10–20%), and O 6 ‐methylguanine ( O 6 ‐MeG; 5–10%) (Bobola et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…BER is the predominant DNA repair system in mammalian cells and repairs small cytotoxic DNA base lesions resulting from oxidized, alkylated, or deaminated nucleotides (Kim and Wilson, 2012; Krokan and Bjoras, 2013). The remaining 5–10% of TMZ‐induced DNA‐methylated lesions occur as O 6 ‐MeG which is the substrate for the enzyme O 6 ‐methylguanine‐DNA methyltransferase (MGMT) (Sarkaria et al ., 2008). The TMZ‐induced purine base alkylations N 3 ‐MeA and N 7 ‐MeG are the substrates for the monofunctional glycosylase N‐methylpurine DNA glycosylase (MPG, also known as alkylpurine‐DNA‐N‐glycosylase [APNG] or 3‐alkyladenine DNA glycosylase [AAG]).…”

Section: Introductionmentioning

confidence: 99%

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

et al. 2018

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The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

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Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma

Cited by 316 publications

References 59 publications

Dual role of the mitochondrial protein frataxin in astrocytic tumors

Dual role of the mitochondrial protein frataxin in astrocytic tumors

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

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