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

by Xavier Thuru, Romain Magnez, Hassiba El-Bouazzati, Gérard Vergoten, Bruno Quesnel and Christian Bailly

Cancers 2022, 14(14), 3368; https://doi.org/10.3390/cancers14143368 - 11 Jul 2022

Cited by 18 | Viewed by 8600

Abstract

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. Full article

(This article belongs to the Special Issue Checkpoint Markers and Cancer Microenvironment: What Do We Know?)

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13 pages, 2159 KB

Open AccessArticle

Azelnidipine Exhibits In Vitro and In Vivo Antiviral Effects against Flavivirus Infections by Targeting the Viral RdRp

by Zhuang Wang, Yunzheng Yan, Qingsong Dai, Yijie Xu, Jiye Yin, Wei Li, Yuexiang Li, Xiaotong Yang, Xiaojia Guo, Miaomiao Liu, Xingjuan Chen, Ruiyuan Cao and Wu Zhong

Viruses 2022, 14(6), 1228; https://doi.org/10.3390/v14061228 - 5 Jun 2022

Cited by 9 | Viewed by 3342

Abstract

Flaviviruses, represented by Zika and dengue virus (ZIKV and DENV), are widely present around the world and cause various diseases with serious consequences. However, no antiviral drugs have been clinically approved for use against them. Azelnidipine (ALP) is a dihydropyridine calcium channel blocker and has been approved for use as an antihypertensive drug. In the present study, ALP was found to show potent anti-flavivirus activities in vitro and in vivo. ALP effectively prevented the cytopathic effect induced by ZIKV and DENV and inhibited the production of viral RNA and viral protein in a dose-dependent manner. Moreover, treatment with 0.3 mg/kg of ALP protected 88.89% of mice from lethal challenge. Furthermore, using the time-of-drug-addition assay, the enzymatic inhibition assay, the molecular docking, and the surface plasmon resonance assay, we revealed that ALP acted at the replication stage of the viral infection cycle by targeting the viral RNA-dependent RNA polymerase. These findings highlight the potential for the use of ALP as an antiviral agent to combat flavivirus infections. Full article

(This article belongs to the Special Issue De Novo Drug Design for Emerging and Reemerging Viruses)

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17 pages, 2625 KB

Open AccessArticle

Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy

by Xiuman Zhou, Ling Jiao, Yuzhen Qian, Qingyu Dong, Yixuan Sun, Wei V. Zheng, Wenshan Zhao, Wenjie Zhai, Lu Qiu, Yahong Wu, Hongfei Wang, Yanfeng Gao and Junhui Chen

Biomolecules 2021, 11(5), 706; https://doi.org/10.3390/biom11050706 - 10 May 2021

Cited by 35 | Viewed by 6319

Abstract

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8⁺ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8⁺ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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14 pages, 222 KB

Open AccessArticle

Validated Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Azelnidipine and Olmesartan in Their Combined Dosage Form

by Jayvadan K. PATEL and Nilam K. PATEL

Sci. Pharm. 2014, 82(3), 541-554; https://doi.org/10.3797/scipharm.1312-14 - 27 Feb 2014

Cited by 23 | Viewed by 3165

Abstract

A simple, rapid, and highly selective RP-HPLC method was developed for the simultaneous determination of Azelnidipine (AZL) and Olmesartan (OLM) drug substances in the fixed dosage strength of 16 mg and 20 mg, respectively. Effective chromatographic separation was achieved using a Hypersil GOLD C18 column (150 mm × 4.6 mm internal diameter, 5 μm particle size) with a mobile phase composed of methanol, acetonitrile, and water in the ratio of 40:40:20 (by volume). The mobile phase was pumped using a gradient HPLC system at a flow rate of 0.5 mL/min, and quantification of the analytes was based on measuring their peak areas at 260 nm. The retention times for Azelnidipine and Olmesartan were about 8.56 and 3.04 min, respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Calibration curves were linear in the ranges of 2–48 μg/mL for Azelnidipine and 2.5–60 μg/mL for Olmesartan with correlation coefficients >0.990. The proposed method proved to be selective and stability-indicating by the resolution of the two analytes from the forced degradation (hydrolysis, oxidation, and photolysis) products. The validated HPLC method was successfully applied to the analysis of AZL and OLM in their combined dosage form. Full article

12 pages, 222 KB

Open AccessArticle

A New Baroreceptor Sensitivity-Restoring Ca-Channel Blocker Diminishes Age-Related Morning Blood Pressure Increase in Hypertensive Patients: Open-Label Monitoring of Azelnidipine Treatment for Hypertension in the Early Morning (At-HOME) Study

by Kazuomi Kario, Masayuki Shirayama, Katsutoshi Hiramatsu, Kazuhito Shiosakai, Mitsunori Sugiyama and Kazuyuki Shimada

Pharmaceuticals 2010, 3(1), 225-236; https://doi.org/10.3390/ph3010225 - 19 Jan 2010

Viewed by 11855

Abstract

Background: Morning blood pressure (BP) surge, which exhibits an age-related increase, is a risk factor for stroke in elderly hypertensive patients, independently of the 24-h BP level. We studied the effect of the new baroreceptor sensitivity (BRS)-restoring Ca-channel blocker (CCB) azelnidipine (AZ) on this age-related morning BP increase. Methods: We conducted a 16-week prospective study to clarify the effect of morning dosing of AZ on home BPs measured in the morning and in the evening in 2,546 hypertensive patients (mean age, 65.1 years; female, 53.6%). Results: At baseline, ME-Dif (morning systolic BP [SBP]–evening SBP) increased with age, independently of ME-Ave (average of the morning and evening SBPs). This age-related increase of ME-Dif was exaggerated by regular alcohol drinking and beta-blocker use. After AZ treatment (14.3 ± 3.6 mg/day), ME-AV and ME-Dif were significantly reduced independently of each other, with reductions of –18.1 ± 15.6 and –2.5 ± 13.2 mmHg, respectively (both p < 0.001). AZ treatment decreased age-related increase in ME-Dif particularly in patients who were regular consumers of alcohol and in beta-blocker users. Conclusions: The new BRS-restoring CCB AZ significantly reduced age-related increase in morning BP and had some potential benefit on cardiovascular protection in hypertension, particularly in elderly patients and/or consumers of alcohol. Full article

(This article belongs to the Special Issue Antihypertensive Drugs)

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