Autophagy Protects from Trastuzumab-Induced Cytotoxicity in HER2 Overexpressing Breast Tumor Spheroids

Rodriguez, C.; Reidel, Sara; Joffé, Elisa D. Bal de Kier; Jasnis, María A.; Fiszman, Gabriel L.

doi:10.1371/journal.pone.0137920

Cited by 39 publications

(37 citation statements)

References 37 publications

(33 reference statements)

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“…Subsequently, Bcl-2 exerts its antiapoptotic effect, and Beclin-1 plays its role in promoting autophagy. In most reports, autophagy can protect cancer cells from apoptosis, by providing nutrition, inducing resistance [21, 22], and so forth.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Protects from Raddeanin A‐Induced Apoptosis in SGC‐7901 Human Gastric Cancer Cells

Teng

Liu

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Raddeanin A (RA) is an extractive from Anemone raddeana Regel, a traditional Chinese medicine. The aim of this study is to assess the efficacy of RA against human gastric cancer (GC) cells (SGC-7901) and explore its mechanism. MTT assay showed that RA inhibition of proliferation of SGC-7901 cells increased in a dose-dependent manner. Flow cytometry analysis and Hoechst 33258 staining showed that RA induced apoptosis on SGC-7901 cells. Meanwhile, it induced autophagy. Western blotting analysis showed that the RA induces apoptosis and autophagy by activating p38 MAPK pathway and inhibiting mTOR pathway. Further studies showed that autophagy inhibition could protect from RA-induced apoptosis in SGC-7901 cells. In conclusion, RA can induce SGC-7901 cell apoptosis and autophagy by activating p38 MAPK pathway. And autophagy can protect SGC-7901 cells from apoptosis induced by RA.

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Section: Discussionmentioning

confidence: 99%

Autophagy Protects from Raddeanin A‐Induced Apoptosis in SGC‐7901 Human Gastric Cancer Cells

Teng

Liu

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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“…Autophagy represents an important cellular-physiologic response. The interplay between autophagy and apoptosis is complex and has been the focus of research [50,51].In most reports, autophagy has been demonstrated to protect cancer cells from apoptosis by providing nutrition and inducing resistance [52,53]. However, excessive autophagy can lead to caspase-independent cell death.…”

Section: Figurementioning

confidence: 99%

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Peng

Wang

Shu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Raddeanin A (RA), an active pharmacological ingredient from Anemone raddeana Regel, plays an important role in tumor suppression. In this study, we assessed the potentially therapeutic effect of RA on glioblastoma and its underlying mechanisms. Methods: Cell viability was examined using the MTT assay. Invasive and migratory capacities were examined using Transwell and wound healing assays. Apoptosis was determined by Hoechst staining, flow cytometry, DCFH-fluorescent probe and immunohistochemical staining. Autophagy was detected by transmission electron microscopy and western blotting. A U251 glioma xenograft model was established to evaluate the effect of RA in vivo. Results: The data demonstrated that RA inhibited viability, and abrogated the invasive/migratory abilities of glioblastoma cells. In addition, RA induced apoptosis by reactive oxygen species (ROS)/ Jun N-terminal kinase (JNK) signaling in glioblastoma. Conversely, the antioxidant N-Acetyl-L-cysteine (NAC) and pan-caspase inhibitor z-VAD-fmk attenuated RA-induced apoptosis by scavenging ROS and inactivating caspase-3. Furthermore, the inhibition of autophagy by 3-MA exacerbated apoptosis through ROS generation and JNK phosphorylation. In vivo, RA exhibited a curative effect on U251-derived xenografts in nude mice. Conclusions: The results of this study suggest that RA suppressed the growth of glioblastoma, thus serving as a promising and potential strategy for glioblastoma chemotherapy.

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“…Several studies including different 3D systems were applied however, little is known regarding 3D breast cancer cell spheroids exposed to radiation although radiotherapy is widely applied for breast cancer therapy .…”

Section: Discussionmentioning

confidence: 99%

Three‐dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer

et al. 2016

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A 3D microtissues using T47D and JIMT‐1 cells were generated to analyze tissue‐like response of breast cancer cells after combined human epidermal growth factor receptor 2 (HER2)‐targeted treatment and radiation. Following lentiviral knockdown of HER2, we compared growth rate alterations using 2D monolayers, 3D microtissues, and mouse xenografts. Additionally, to model combined therapeutic strategies, we treated HER2‐depleted T47D cells and 3D microtissues using trastuzumab (anti‐HER2 antibody) in combination with irradiation. Comparison of HER2 knockdown with corresponding controls revealed growth impairment due to HER2 knockdown in T47D 2D monolayers, 3D microtissues, and xenografts (after 2, 12, and ≥40 days, respectively). In contrast, HER2 knockdown was less effective in inhibiting growth of trastuzumab‐resistant JIMT‐1 cells in vitro and in vivo. Combined administration of trastuzumab and radiation treatment was also analyzed using T47D 3D microtissues. Administration of both, radiation (5 Gy) and trastuzumab, significantly enhanced the growth inhibiting effect in 3D microtissues. To improve the predictive power of potential drugs—as single agents or in combination—here, we show that regarding tumor growth analyses, 3D microtissues are highly comparable to outcomes derived from xenografts. Considering increased limitations for animal experiments on the one hand and strong need of novel drugs on the other hand, it is indispensable to include highly reproducible 3D microtissue platform in preclinical analyses to validate more accurately the capacity of future drug‐combined radiotherapy.

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Autophagy Protects from Trastuzumab-Induced Cytotoxicity in HER2 Overexpressing Breast Tumor Spheroids

Cited by 39 publications

References 37 publications

Autophagy Protects from Raddeanin A‐Induced Apoptosis in SGC‐7901 Human Gastric Cancer Cells

Autophagy Protects from Raddeanin A‐Induced Apoptosis in SGC‐7901 Human Gastric Cancer Cells

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Three‐dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer

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