Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

García-Cano, Jesús; Ambroise, Gorbatchev; Pascual-Serra, Raquel; Carrión, Maria Carmen; Serrano-Oviedo, Leticia; Ortega-Muelas, Marta; Cimas, Francisco J.; Sabater, S.; Ruiz-Hidalgo, Marı́a José; Sanchez-Perez, Isabel; Más, Antonio; Jalón, Félix A.; Vázquez, Aimé; Sánchez‐Prieto, Ricardo

doi:10.18632/oncotarget.3902

Cited by 43 publications

(38 citation statements)

References 79 publications

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“…Autophagy is one of the underlying mechanisms of tumor resistance to chemotherapy . In the present study, NB showed moderate sensitivity to PTX, as demonstrated in vivo in a previous study .…”

Section: Discussionsupporting

confidence: 85%

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin‐related protein 14‐mediated autophagy

Zhen¹,

Yang

et al. 2017

Cancer Science

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Paclitaxel is not as effective for neuroblastoma as most of the front‐line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel‐associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy‐associated proteins were assessed by western blot. Autophagy was induced and the autophagy‐associated proteins LC3‐I, LC3‐II, Beclin 1, and thioredoxin‐related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1‐mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel‐induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel‐induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14.

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Section: Discussionsupporting

confidence: 85%

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin‐related protein 14‐mediated autophagy

Zhen¹,

Yang

et al. 2017

Cancer Science

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“…Apoptosis is the primary mechanism underlying the action of anticancer drugs (17). Autophagy, the intracellular degradation of cytoplasmic components, serves an intricate and paradoxical role in tumor chemotherapy (18,19). The results of the present study indicated that autophagy may act as a pro-survival mechanism in the anticancer action of thioridazine.…”

Section: Discussionmentioning

confidence: 58%

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Yong

Tian

et al. 2017

Oncol Lett

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Abstract. Dopamine receptor 2 (DR2) may be a biomarker for various types of cancer. Ovarian cancer cells overexpress DR2; therefore, blocking DR2 may be a novel treatment strategy for ovarian cancer. Thioridazine, a DR2 blocker, has antineoplastic activity in a variety of cancer cells. In view of the requirement for novel therapeutic agents in ovarian cancer, the present study aimed to determine the potential effects of thioridazine in vitro and in vivo. It was revealed that the DR2 blocker thioridazine induced cell death in a dose-dependent manner in ovarian cancer cells. Thioridazine treatment induced apoptosis and autophagy, which may be attributed to an increased level of reactive oxygen species and associated DNA damage. Additionally, the expression of various proteins increased with oxidative stress, including nuclear factor E2-related factor 2, which is a pivotal transcriptional factor involved in cellular responses to oxidative stress. Heme oxygenase 1, NAPDH quinone dehydrogenase 1 and hypoxia inducible factor-1α and phosphorylated (p)-protein kinase B expression was significantly decreased, and the expression level of p-extracellular signal-related kinases and p-P38 was increased. Using 3-methyl adenine to inhibit autophagy caused the rate of apoptosis to increase. Thioridazine inhibited the growth of SKOV3 xenografts in nude mice. The present study demonstrated that the DR2 blocker thioridazine exhibited anticancer effects in vitro and in vivo, suggesting that thioridazine may be used as a potential drug in ovarian cancer therapy. IntroductionEpithelial ovarian cancer is the leading cause of mortality among gynecological types of cancer. Surgical debulking combined with chemotherapy is the standard therapeutic strategy. However, the relapse rate is high, primarily due to the development of chemotherapy resistance (1), therefore, novel modalities must be explored.Dopamine receptor (DR) expression may be associated with the development of various types of cancer. Patients with schizophrenia who receive DR antagonists have a reduced incidence of cancer of the rectum, colon, prostate and uterine cervix (2,3). Patients with Parkinson's disease, which functionally similar to disease-induced DR antagonism, also have a lower incidence of cancer. It was hypothesized that DR may be a biomarker for cancer (4). Knockdown/blocking of DR2 inhibited the proliferation of cancer cells, including cancer stem cells (5). This suggested that DR2 may be a treatment target for types of cancer that expresses dopamine receptor 2.Thioridazine is a DR2 antagonist and has been clinically approved to treat schizophrenia and other psychotic disorders (6). Of note, thioridazine exhibits anticancer action in breast cancer, leukemia, hepatoma and cervical carcinoma (5,7-9). Ovarian cancer cells express a number of DRs, with the exception of DR3 (10), suggesting that thioridazine may be used to treat ovarian cancer. In the present study, the effects of thioridazine on ovarian cancer were explored in vitro and in vivo. The findings sug...

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“…In contrast to the studies cited above in support of the cytoprotective function of cisplatin-induced autophagy, work by another team of investigators demonstrated that inhibition of autophagy using either 3-MA or silencing of the autophagy gene, ATG5 , did not significantly alter the influence of cisplatin on viability of H460 cells, indicative of a non-cytoprotective function of autophagy 36 . Furthermore, when autophagy was inhibited either pharmacologically (3-MA) or genetically (silencing of ATG5 ) in p53-null H1299 cells (A549 and H460 cells are wild type in p53), an unexpected reduction of sensitivity to cisplatin was observed, again supporting a cytotoxic function of autophagy.…”

Section: Chemotherapy-induced Autophagymentioning

confidence: 68%

Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer

Saleh

Cuttino

Gewirtz

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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BACKGROUND Lung cancer is the leading cause of cancer-related death worldwide. In addition to surgical resection, which is considered first-line treatment at early stages of the disease, chemotherapy and radiation are widely used when the disease is advanced. Of multiple responses that may occur in the tumor cells in response to cancer therapy, the functional importance of autophagy remains equivocal; this is likely to restrict current efforts to sensitize this malignancy to chemotherapy and/or radiation by pharmacological interference with the autophagic response. SCOPE OF REVIEW In this review, we attempt to summarize the current state of knowledge based on studies that evaluated the function of autophagy in non-small cell lung cancer (NSCLC) cells in response to radiation and the most commonly used chemotherapeutic agents. MAJOR CONCLUSIONS In addition to the expected prosurvival function of autophagy, where autophagy inhibition enhances the response to therapy, autophagy appears also to have a “non-cytoprotective” function, where autophagy blockade does not affect cell viability, clonogenicity or tumor volume in response to therapy. In other cases, autophagy may actually mediate drug action via expression of its cytotoxic function. GENERAL SIGNIFICANCE These observations emphasize the complexity of autophagy function when examined in different tumor cell lines and in response to different chemotherapeutic agents. A more in-depth understanding of the conditions that promote the unique functions of autophagy is required in order to translate preclinical findings of autophagy inhibition to the clinic for the purpose of improving patient response to chemotherapy and radiation.

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Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

Cited by 43 publications

References 79 publications

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin‐related protein 14‐mediated autophagy

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin‐related protein 14‐mediated autophagy

DR2 blocker thioridazine: A promising drug for ovarian cancer therapy

Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer

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