Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells

Xu, Ye; Yu, Huimei; Qin, Hanjiao; Kang, Jinsong; Yu, Chaoqin; Zhong, Jian‐Jiang; Su, Jing; Li, Hongyan; Sun, Liankun

doi:10.1016/j.canlet.2011.09.034

Cited by 139 publications

(126 citation statements)

References 56 publications

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“…Exposure to 2-deoxyglucose, which induces the upregulation of UPR/GRP78, followed by cisplatin treatment, demonstrated that cisplatin enhanced the mitochondria-mediated apoptosis cascade through the activation of caspase-2 and the downregulation of the expression of DNA damage-repairing genes (23). In our previous studies, we demonstrated that cisplatin treatment induced significant ER stress, upregulation of GRP78, PDI and CHOP and activation of caspase-4 in various cancer cell lines, indicating that cisplatin may induce apoptosis through the ER stress pathway (24,25).…”

Section: Er Stress Is Involved In Cisplatin-induced Cell Death and Ismentioning

confidence: 95%

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A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

Wang

2013

Molecular and Clinical Oncology

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Abstract. Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of solid tumors. However, its side effects and acquired resistance gained during the course of treatment may limit its usage. It is generally considered to be a cytotoxic drug that kills cancer cells by damaging their DNA and inhibiting DNA synthesis to induce apoptosis via the mitochondrial death pathway or through plasma membrane disruption, triggering the Fas death receptor pathway. The endoplasmic reticulum (ER) is one of the most important protein-folding compartments within the cell and an intracellular Ca 2+ storage organelle. The ER contains a number of molecular chaperones, which may play an important role in determining cellular sensitivity to ER stress and apoptosis. The aim of this review was to summarize our current understanding regarding the mechanisms of ER stress response by which cisplatin induces cell death and the basis for cisplatin resistance. Various aspects were addressed, including the two-way regulation of ER stress, the involvement of ER stress in cisplatin-induced cell death and drug resistance and the drugs enhancing cisplatin-induced cell death by interfering with ER stress. An understanding of how ER stress signaling pathways regulate cisplatin-induced cell death may enable the development of more effective therapeutic strategies for the treatment of cancer.

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Section: Er Stress Is Involved In Cisplatin-induced Cell Death and Ismentioning

confidence: 95%

“…In addition, autophagy blockage or ER stress elevation increased the sensitivity of HeLa cells to cisplatin. Autophagy inhibition or ER stress induction may represent therapeutic targets for the improvement of cisplatin efficacy (24).…”

Section: Interference Of Er Stress May Enhance Cisplatin-induced Tumomentioning

confidence: 99%

A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

Wang

2013

Molecular and Clinical Oncology

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“…Following DNA damage, cells either repair the damage and start progressing through the cell cycle or, when the damage cannot be repaired, the cells proceed to apoptosis (4). The main death pathway activated by specific cellular damage induced by cisplatin is a caspase-dependent intrinsic apoptotic pathway that involves mitochondria and the endoplasmic reticulum (ER) (7,(23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…The ER was recently reported to be a cytosolic target of cisplatin-induced apoptosis via the ER stress pathway; sustained and unabated ER stress induces caspase-mediated apoptosis (7,27,34). In addition, ER stress and mitochondrial dysfunction have also been suggested to cooperatively regulate apoptotic-signaling cascades (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Based on the mechanism of action of cisplatin-induced cell death, modifications to the combination methods used in chemotherapy are required to reduce the side-effects and increase the therapeutic effects of cisplatin. Autophagy inhibitors, such as 3-methyladenine and chloroquine, have been shown to effectively enhance cisplatin cytotoxity (5)(6)(7)(8). Additional agents have been recently assessed such as bortezomib (PS-341, Velcade), a proteasome inhibitor (9,10), and histone acetyltransferase inhibitor, suberoylanilide hydroxamic acid (SAHA) (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Wang

Ding

et al. 2013

Oncology Reports

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Abstract. Cisplatin (cis-diamminedichloroplatinum II, CDDP) acts as a therapeutic agent by initiating cellular apoptosis. However, side-effects and drug resistance limit the clinical use of cisplatin. Numerous studies have focused on the drug-target interactions, cellular pharmacology and pharmacokinetics of cisplatin. Newly developed treatment strategies are needed in order to be used in combination with cisplatin, with the aim to minimize toxicity and to circumvent cisplatin resistance. Ammonium chloride (NH 4 Cl) is widely used in various areas, but its use as a combination agent with cisplatin for the treatment of cancer cells has not been previously reported. In the present study, we showed that NH 4 Cl could be potentially used as an effective agent in cisplatin combination treatment of HeLa human cervical cancer (HCC) cells. Cisplatin was found to inhibit cell growth, as well as to induce cell apoptosis and DNA double-strand breaks. In addition, treatment with NH 4 Cl increased the rate of cell apoptosis and the activation of caspase-3. Particularly, we found that NH 4 Cl treatment increased cisplatin-induced phosphorylation of H 2 AX. In conclusion, our data indicate that NH 4 Cl enhances cisplatin cytotoxicity through increased DNA damage in HeLa HCC cells. IntroductionCisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents widely used for the treatment of solid tumors. However, the side-effects of cisplatin chemotherapy and resistance during the course of the treatment limit its clinical use (1-3). Cisplatin is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death predominantly by inducing apoptosis (4). Based on the mechanism of action of cisplatin-induced cell death, modifications to the combination methods used in chemotherapy are required to reduce the side-effects and increase the therapeutic effects of cisplatin. Autophagy inhibitors, such as 3-methyladenine and chloroquine, have been shown to effectively enhance cisplatin cytotoxity (5-8). Additional agents have been recently assessed such as bortezomib (PS-341, Velcade), a proteasome inhibitor (9,10), and histone acetyltransferase inhibitor, suberoylanilide hydroxamic acid (SAHA) (11,12). Some of these agents have been shown to confer sensitizing effects to cisplatin combination therapy.Ammonium chloride (NH 4 Cl) is an agent used for the treatment of metabolic alkalosis in clinical practice (13). NH 4 Cl was recently used as an autophagy inhibitor in in vitro studies, where it was found to affect the pH of lysosomes and to disturb the activity of autolysosomes (14-16). In the present study, we used NH 4 Cl combined with cisplatin to investigate the potentially effective use of NH 4 Cl as an agent in cisplatin combination chemotherapy.In the present study, we tested the hypothesis that the use of NH 4 Cl increases the apoptosis induced by cispl...

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Cascade‐Amplifying Synergistic Therapy for Intracranial Glioma via Endogenous Reactive Oxygen Species‐Triggered “All‐in‐One” Nanoplatform

Zhu

et al. 2021

Adv Funct Materials

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Targeted delivery of drug-loaded nanoparticles to brain tumors is exceptionally difficult due to the blood-brain barrier (BBB). In addition, several chemotherapeutic drugs induce autophagy, which protects the cells from apoptosis and mitigates the therapeutic effect. A novel "all-in-one" nanoparticles (AMPTL) consisting of endogenous reactive oxygen species-cleavable thioketal linkers conjugated to paclitaxel (PTX) and autophagy inhibitor 3-methyladenine, and angiopep-2 peptide-modified DSPE-PEG 2K is developed. AMPTL inhibits autophagy in the C6 glioma cells, as indicated by fewer autophagic vesicles, lower LC3-II expression and accumulation of SQSTM1/ P62, and significantly upregulates p53 and the pro-apoptotic Bax and cleaved caspase-3 proteins. In addition, AMPTL treatment induces cell cycle arrest at the G2/M phase. Thus, inhibition of autophagy in the AMPTL-treated glioma cells sensitizes them to PTX-induced cell cycle arrest and apoptosis. Furthermore, focused pulse ultrasound and microbubbles enhances the delivery of AMPTL to intracranial glioma tissues by reversibly opening the BBB, which significantly inhibits xenograft growth and markedly improves survival rates of the tumor-bearing mice. Taken together, combining non-invasive BBB opening with autophagy inhibitors and chemotherapeutic drugs can achieve cascade-amplifying synergistic therapeutic effects against glioma.

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Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells

Cited by 139 publications

References 56 publications

A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Cascade‐Amplifying Synergistic Therapy for Intracranial Glioma via Endogenous Reactive Oxygen Species‐Triggered “All‐in‐One” Nanoplatform

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