Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

Li, Yue; Tian, Wei; Yue, Dongsheng; Chen, Chen; Li, Chenguang; Zhang, Zhenfa; Wang, Changli

doi:10.1155/2021/5548130

Cited by 16 publications

(13 citation statements)

References 69 publications

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“…Induction of acute ER stress using thapsigargin impairs mitochondrial function in mouse and rat hearts [ 3 , 4 , 5 ]. An increase in ER stress with doxorubicin or bevacizumab treatment also results in mitochondrial dysfunction [ 6 , 7 ]. Mitochondrial dysfunction contributes to cardiac injury in many pathological conditions including aging and heart failure [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Chen¹,

Thompson²,

Hu³

et al. 2022

Life

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Background: Induction of acute ER (endoplasmic reticulum) stress using thapsigargin contributes to complex I damage in mouse hearts. Thapsigargin impairs complex I by increasing mitochondrial calcium through inhibition of Ca2+-ATPase in the ER. Tunicamycin (TUNI) is used to induce ER stress by inhibiting protein folding. We asked if TUNI-induced ER stress led to complex I damage. Methods: TUNI (0.4 mg/kg) was used to induce ER stress in C57BL/6 mice. Cardiac mitochondria were isolated after 24 or 72 h following TUNI treatment for mitochondrial functional analysis. Results: ER stress was only increased in mice following 72 h of TUNI treatment. TUNI treatment decreased oxidative phosphorylation with complex I substrates compared to vehicle with a decrease in complex I activity. The contents of complex I subunits including NBUPL and NDUFS7 were decreased in TUNI-treated mice. TUNI treatment activated both cytosolic and mitochondrial calpain 1. Our results indicate that TUNI-induced ER stress damages complex I through degradation of its subunits including NDUFS7. Conclusion: Induction of the ER stress using TUNI contributes to complex I damage by activating calpain 1.

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Section: Introductionmentioning

confidence: 99%

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Chen¹,

Thompson²,

Hu³

et al. 2022

Life

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“…Yue Li et al. demonstrated that bevacizumab-mediated cardiotoxicity is associated with mitochondrial dysfunction and ERK pathway inactivation ( 31 ). Rituximab has also been shown to cause adverse cardiac events including arrhythmia and, on occasion, myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

Takotsubo Syndrome (TTS) in Onco-Hematologic Patients: Retrospective Analysis and Focus on the Correlation or Not With Anticancer Drugs. Case Reports and Review of the Literature

et al. 2022

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Takotsubo syndrome (TTS) is an uncommon cardiovascular condition also known as stress-induced cardiomyopathy or broken heart disease. The syndrome, characterized by acute non-coronary segmental ventricular dysfunction, commonly occurs as a reaction to severe emotional or physical stress and can cause significant problems. Several classes of chemotherapeutic agents that are known to be cardiotoxic have been shown to be associated with TTS in cancer patients. Describing a case of TTS from chemotherapy and/or monoclonal antibody is important because these drugs are widely used and their temporary or permanent suspension could compromise the success of treatment. The detection and reporting of suspected adverse drug reactions in clinical practice are the foundations of postmarketing surveillance. We performed a retrospective analysis of a large number of patients followed at our cancer centre to identify drugs that could lead to the onset of TTS, focusing our attention on 2 monoclonal antibodies, bevacizumab and rituximab plus chemotherapy. A search was carried out for the word “Takotsubo” in database sources such as in PubMed, in medical oncology, radiology and cardiology electronic clinical records. From October 2007 to March 2021, of the 79,005 patients seen or treated for any kind of malignancy at our institute, 9 had a diagnosis of TTS (4 before and 5 after the diagnosis of malignancy). Only 2 patients had TTS after treatment with the anticancer drugs, bevacizumab and rituximab plus chemotherapy. These two patients were hospitalised, one for subocclusion while the other for pulmonary embolism (PE) with a life threatening condition and in need of intravenous catecholamines. For both patients, an ECG, echocardiography and coronary angiography were performed as well as blood tests with a subsequent diagnosis of TTS and both received cardiological treatment with resolution of the clinical picture. A reassessment of the two cases found that a subocclusion and intravenous catecholamines appeared to be the most likely triggers. In conclusion, TTS is rare in cancer patients. Identifying TTS triggers could be useful because it could induce therapeutic changes.

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“…A cell viability test was performed by CCK‐8 kit to evaluate the proliferation of SCLC cells under pazopanib treatment, as previously described 19 . In brief, 5 × 10 3 cells/well were cultured in 96‐well plates in 180 μl of complete medium.…”

Section: Methodsmentioning

confidence: 99%

“…A cell viability test was performed by CCK-8 kit to evaluate the proliferation of SCLC cells under pazopanib treatment, as previously described. 19 In brief, 5 Â 10 3 cells/well were cultured in 96-well plates in 180 μl of complete medium. Different concentrations of pazopanib in 20 μl of complete medium were added to each well (range 0-30 μM).…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress

Chen

Liu

et al. 2022

Thoracic Cancer

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Background: Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear. Methods: Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice. Results: Pazopanib dose-and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanibmediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor. Conclusion: Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated. K E Y W O R D S apoptosis, endoplasmic reticulum stress (ER-stress), Pazopanib, reactive oxygen species (ROS), small cell lung cancer (SCLC)

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Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

Cited by 16 publications

References 69 publications

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Takotsubo Syndrome (TTS) in Onco-Hematologic Patients: Retrospective Analysis and Focus on the Correlation or Not With Anticancer Drugs. Case Reports and Review of the Literature

Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress

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