Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1

Pan, Xiaohui; Li, Run; Guo, Hongjie; Zhang, Wenxin; Xu, Xiaqing; Chen, Xi; Ding, Ling

doi:10.3389/fphar.2020.539261

Cited by 21 publications

(14 citation statements)

References 34 publications

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“…Mechanistically, elesclomol forms an elesclomol-Cu (II) complex by chelating copper (Cu) outside of cells, which rapidly transports copper into the mitochondria, thus inducing mitochondrial ROS accumulation [ 472 , 473 ]. Other types of metal chelators, including zinc and calcium chelating agents, have also been recognized as effective antitumor agents [ 474 , 475 ].…”

Section: Strategies For Overcoming Mitochondria-targeting Bottlenecks...mentioning

confidence: 99%

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

et al. 2022

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Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.

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Section: Strategies For Overcoming Mitochondria-targeting Bottlenecks...mentioning

confidence: 99%

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

et al. 2022

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“…Immunotherapies are also on the rise in cancer treatment. One study found that blocking calcium channels can suppress the transcription of programmed death-ligand 1 (PD-L1) and enhance natural killers cells’ ability to eliminate the cancer [ 88 ]. Chemotherapies that target calcium signaling, similar to those used against breast cancer, such as cisplatin and doxorubicin, were found to be synergistic in combination with EGFR inhibitors (gefitinib and erlotinib) and to prolong patient survival in the clinic [ 89 ].…”

Section: Combination Therapymentioning

confidence: 99%

Role of Calcium Homeostasis in Modulating EMT in Cancer

Jones

Hazlehurst

2021

Biomedicines

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Calcium is essential for cells to perform numerous physiological processes. In cancer, the augmentation of calcium signaling supports the more proliferative and migratory cells, which is a characteristic of the epithelial-to-mesenchymal transition (EMT). By genetically and epigenetically modifying genes, channels, and entire signaling pathways, cancer cells have adapted to survive with an extreme imbalance of calcium that allows them to grow and metastasize in an abnormal manner. This cellular remodeling also allows for the evasion of immune surveillance and the development of drug resistance, which lead to poor prognosis in patients. Understanding the role calcium flux plays in driving the phenotypes associated with invasion, immune suppression, metastasis, and drug resistance remains critical for determining treatments to optimize clinical outcomes and future drug discovery.

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“…This has been demonstrated with the CCB lercanidipine that is capable of down-regulating PD-L1 in lung cancer cells (NCI-H1299 cells and NCI-H460 cells) and enhancing the killing ability of T cells. A similar capacity to induce T cell-mediated cancer cell death was then evidenced with azelnidipine and amlodipine, although these two other CCBs were slightly less potent than lercanidipine [ 64 ] ( Figure 3 b). In another similar study, amlodipine was found to induce of PD-L1 degradation and antitumor immunity in a mouse MC38 tumor model.…”

Section: Drug Repositioning To Target the Pd-1/pd-l1 Checkpointmentioning

confidence: 70%

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

Thuru

Magnez

El-Bouazzati

et al. 2022

Cancers

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Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer.

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Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1

Cited by 21 publications

References 34 publications

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Role of Calcium Homeostasis in Modulating EMT in Cancer

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

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