Natural Reno-Protective Agents against Cyclosporine A-Induced Nephrotoxicity: An Overview

Ibrahim, Sabrin R. M.; Abdallah, Hossam M.; El-Halawany, Ali M.; Mohamed, Gamal A.; Alhaddad, Aisha; Samman, Waad A.; Alqarni, Ali; Rizq, Akaber T.; Ghazawi, Kholoud F.; El-Dine, Riham Salah

doi:10.3390/molecules27227771

Cited by 6 publications

(2 citation statements)

References 105 publications

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“…Despite distinctive pharmacological mechanisms [ 10 – 12 , 38 , 39 ], CPYPP, CsA, and curcumin were shown for the first time to induce cancer cell paraptosis in a ROS- and CDK7/CDK9-dependent manner. The finding that CDK7/CDK9 interacts with HSPs to arrest the cell cycle at the G2/M phase in paraptotic development extends the role of CDKs to the upstream step in cell cycle progression [ 19 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

Chiang,

Chang,

Chen

et al. 2024

Cell Biosci

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Background Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown. Methods Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. Results CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth. Conclusions We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

Chiang,

Chang,

Chen

et al. 2024

Cell Biosci

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“…Cyclosporine is an immunosuppressive agent that speci cally targets T lymphocytes, and is frequently utilized in clinical settings to prevent graft rejection in liver, kidney, and heart transplantation. Additionally, it can be combined with steroids to treat immune-related disorders [13].…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine successful treated Steroid-resistant checkpoint inhibitor-related pneumonitis: A case report

Deng,

Guan,

et al. 2023

Preprint

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Background Immune checkpoint inhibitor-related pneumonitis (CIP) stands out as a particularly severe adverse event caused by cancer immunotherapy, with a substantial real-world incidence ranging from 13–19%. While systemic corticosteroids represent the standard treatment for CIP, therapeutic options become limited in cases where patients do not respond to steroid therapy. Such patients are classified as having steroid-resistant CIP, often associated with a poor prognosis. This case study provides insight into the symptoms, diagnostic process, and treatment approach for steroid-resistant CIP. Notably, successful management is demonstrated through the utilization of cyclosporine, highlighting its potential mechanisms of action in effectively treating steroid-resistant CIP. Case description: Here, we present the case of a 53-year-old male patient diagnosed with stage IVA non-small cell lung cancer(NSCLC), who experienced elevated fever, cough, and difficulty in breathing subsequent to immunotherapy treatment. Based on his medical history, clinical presentation, and imaging results, the patient was confirmed to have CIP. The patient's condition demonstrated improvement upon administration of corticosteroids; however, during the subsequent tapering of corticosteroid treatment, a resurgence of CIP occurred, eventually leading to a state of respiratory failure. Consequently, we arrived at the diagnosis of steroid-resistant CIP, prompting the implementation of a combination therapy involving cyclosporine in conjunction with corticosteroids to establish stable disease control. As the corticosteroid dosage was systematically reduced, the patient continued to exhibit a favorable response with no observable recurrence. Conclusions This marks the inaugural instance of effectively managing steroid-resistant CIP through the synergistic employment of cyclosporine and corticosteroids. Presently, cases of steroid-resistant CIP remain infrequent, necessitating vigilant and meticulous monitoring within clinical settings. Notably, there exists no distinct guideline specifying a singular agent for rescuing patients insensitive to corticosteroid therapy. Thus, cyclosporine emerges as a promising and efficacious treatment alternative for individuals unresponsive to corticosteroid intervention in the context of CIP.

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Averrhoa carambola L. fruit and stem metabolites profiling and immunostimulatory action mechanisms against cyclosporine induced toxic effects in rat model as analyzed using UHPLC/MS-MS-based chemometrics and bioassays

S. Ramadan,

M. Fayek,

M. El-Sayed

et al. 2023

Food and Chemical Toxicology

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Natural Reno-Protective Agents against Cyclosporine A-Induced Nephrotoxicity: An Overview

Cited by 6 publications

References 105 publications

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells

Cyclosporine successful treated Steroid-resistant checkpoint inhibitor-related pneumonitis: A case report

Averrhoa carambola L. fruit and stem metabolites profiling and immunostimulatory action mechanisms against cyclosporine induced toxic effects in rat model as analyzed using UHPLC/MS-MS-based chemometrics and bioassays

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