Therapeutic Tolerance, Hemodynamic Effects, and Oral Dose Kinetics of Dilazep Dihydrochloride in Hypertensive Patients

Sambhi, Mohinder P.; Kannan, R.; Thananopavarn, Chalemphol; Ookhtens, Murad; Gudenzi, M.

doi:10.1002/jps.2600780404

Cited by 4 publications

(1 citation statement)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This led us to examine for agents with a structural similarity that could be used clinically. Via in silico screen, we identified dilazep, a drug that has been used as a vasodilator (mechanistically works as an adenosine reuptake inhibitor ( Deguchi et al 1997 )) in patients with hypertension, cardiovascular, and renovascular disorders in Japan and several European countries ( Sambhi et al 1989 ). Our studies in PC cells demonstrate that dilazep is able to inhibit proliferation and AR signaling in both androgen-dependent cells and castration-resistant PC cell lines in vitro and is active in an in vivo patient-derived xenograft (PDX) model.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Kaochar

Rusin

Foley

et al. 2022

Endocrine-Related Cancer

View full text Add to dashboard Cite

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2,650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity assays (MTT), global gene expression analysis, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Kaochar

Rusin

Foley

et al. 2022

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

Dilazep synergistically reactivates latent HIV-1 in latently infected cells

et al. 2014

View full text Add to dashboard Cite

The long-lived latently infected cells persist in spite of prolonged highly active anti-retroviral therapy and present a major barrier to a cure of human immunodeficiency virus type 1 (HIV-1) infection. Elimination of this reservoir requires reactivation of the latent virus. None of the current agents can safely and effectively reactivate latent HIV-1 reservoirs. Dilazep, a nucleoside transport inhibitor, is used to treat ischemic dysfunction. However, little is known about the effect of dilazep in inducing HIV expression in latently infected cells. Using the Jurkat T cell model of HIV-1 latency, we found that dilazep effectively reactivates latent HIV-1 gene expression in a dose manner. We observed that dilazep synergistically reactivated latent HIV-1 transcription with valproic acid. We also found that dilazep activates viral latency without inducing cell surface activation markers CD25 and CD69 activation. In summary, dilazep, alone or in combination with VPA, could be useful in future eradication strategies.

show abstract

Cladribine as a Potential Object of Nucleoside Transporter-Based Drug Interactions

Hermann¹,

Krajcsi²,

Fluck

et al. 2021

Clin Pharmacokinet

View full text Add to dashboard Cite

Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad ® ), administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years), are used to treat patients with relapsing multiple sclerosis. Cladribine has been shown to be a substrate of various nucleoside transporters (NTs). Intestinal absorption and distribution of cladribine throughout the body appear to be essentially mediated by equilibrative NTs (ENTs) and concentrative NTs (CNTs), specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Other efficient transporters of cladribine are the ABC efflux transporters, specifically breast cancer resistance protein, which likely modulates the oral absorption and renal excretion of cladribine. A key transporter for the intracellular uptake of cladribine into B and T-lymphocytes is ENT1 with ancillary contributions of ENT2 and CNT2. Transporter-based drug interactions affecting absorption and target cellular uptake of a prodrug such as cladribine are likely to reduce systemic bioavailability and target cell exposure, thereby possibly hampering clinical efficacy. In order to manage optimized therapy, i.e., to ensure uncompromised target cell uptake to preserve the full therapeutic potential of cladribine, it is important that clinicians are aware of the existence of NT-inhibiting medicinal products, various lifestyle drugs, and food components. This article reviews the existing knowledge on inhibitors of NT, which may alter cladribine absorption, distribution, and uptake into target cells, thereby summarizing the existing knowledge on optimized methods of administration and concomitant drugs that should be avoided during cladribine treatment.

show abstract

Therapeutic Tolerance, Hemodynamic Effects, and Oral Dose Kinetics of Dilazep Dihydrochloride in Hypertensive Patients

Cited by 4 publications

References 8 publications

Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Inhibition of GATA2 in prostate cancer by a clinically available small molecule

Dilazep synergistically reactivates latent HIV-1 in latently infected cells

Cladribine as a Potential Object of Nucleoside Transporter-Based Drug Interactions

Contact Info

Product

Resources

About