Pharmacodynamic modelling reveals synergistic interaction between docetaxel and SCO-101 in a docetaxel-resistant triple negative breast cancer cell line

Nøhr-Nielsen, Asbjørn; Bagger, Sofie O.; Brünner, Nils; Stenvang, Jan; Lund, Trine Meldgaard

doi:10.1016/j.ejps.2020.105315

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…Importantly, SPHINX‐31 did not affect normal haematopoiesis in vivo [ 50 ], thus providing encouraging results in relation to its clinical safety. SCO‐101 is a drug described as an inhibitor of ATP‐Binding Cassette (ABC) efflux pumps and of SRPK1 [ 166 ], which displayed anti‐cancer potential in combination with docetaxel in triple negative breast cancer cells [ 167 ]. More recently, an irreversible SRPK1 inhibitor (SRPKIN) was reported to cause strong antiangiogenic effects in a mouse model of choroidal neovascularisation, a form of age‐related macular degeneration that is correlated to potent VEGF‐splicing modulation [ 168 ].…”

Section: Inhibition Of Splicing Factor Kinases: Emerging Therapeutic Opportunitiesmentioning

confidence: 99%

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

2021

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Alternative splicing and polyadenylation represent two major steps in pre-mRNA processing, which ensure proper gene expression and diversification of human transcriptomes. Deregulation of these processes concurs to oncogenic programs involved in onset, progression and evolution of human cancers, which often result in acquisition of resistance to existing therapies. On the other hand, cancer cells frequently increase their transcriptional rate and develop a transcriptional addiction, which imposes a high stress on the pre-mRNA processing machinery and establishes a therapeutically exploitable vulnerability. A prominent role in fine-tuning pre-mRNA processing mechanisms is played by three main families of protein kinases: SRPK, CLK and CDK. These kinases phosphorylate the RNA polymerase, splicing factors and regulatory proteins involved in cleavage and polyadenylation of the nascent transcripts. The activity of SRPKs, CLKs and CDKs can be altered in cancer cells and their inhibition was shown to exert anticancer effects. In this review, we describe key findings that have been reported on these topics and discuss challenges and opportunities of developing therapeutic approaches targeting splicing factor kinases.

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Section: Inhibition Of Splicing Factor Kinases: Emerging Therapeutic Opportunitiesmentioning

confidence: 99%

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

2021

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“…Six cohorts with 8 volunteers each; 2 received placebo and 6 received SCO-101 (see Table 1). Five cohorts consisted 125 (7) 70 (6) 128 775 (12) 124 (10) 74 (8) 125 (8) 69 (10) 121 (8) 75 4124 (12) 75 (6) 127 (8) 73 7125 (12) 75 (5) 125 (12) 69 (11) 108 (9) 65 (9) Note: All data are shown as means (SD).…”

Section: Trialmentioning

confidence: 99%

“…The interest in SCO-101 was rekindled because SCO-101 was shown to inhibit the proliferation/migration of cancer cell lines, 4 and recent pre-clinical cancer models indicate that it increases the potency of certain forms of cytotoxic chemotherapy and appears to revert chemoresistance to taxanes, topoisomerase I inhibitors, and the antiestrogens tamoxifen and fulvestrant. [5][6][7][8][9][10] The reported mechanisms of action are inhibition of drug efflux pumps (ABCG2) and the Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1) leading to increased accumulation of chemotherapy and thus increased cytotoxicity (data not shown).…”

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confidence: 99%

Four phase 1 trials to evaluate the safety and pharmacokinetic profile of single and repeated dosing of SCO‐101 in adult male and female volunteers

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Stenvang

et al. 2020

Basic Clin Pharma Tox

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SCO‐101 (Endovion) was discontinued 20 years ago as a new drug under development against sickle cell anaemia. Data from the phase 1 studies remained unpublished. New data indicate that SCO‐101 might be efficacious as add‐on therapy in cancer. Thus, we report the results from the four phase 1 trials performed between 2001 and 2002. Adult volunteers received SCO‐101 or placebo in four independent trials. Adverse events were recorded, and SCO‐101 was determined for pharmacokinetic analysis. Ninety‐two volunteers completed the trials. The most remarkable adverse effect was a transient and dose‐dependent increase in unconjugated bilirubin. Plasma SCO‐101 elimination was approximately log linear, with apparent oral clearances of between 315 and 2103 mL/h for single doses, and between 121 and 2433 mL/h at steady state following oral administration. There was a marked decrease in clearance with increasing dose, and for repeated dose versus single dose. Tmax was greater, and Cmax and AUC∞ were lower in the fed state compared to the fasted state. Exposure was equivalent in males and females and for African Americans and Caucasians. In conclusion, SCO‐101 appears to be a safe drug with a predictable PK profile. Its efficacy as add‐on to standard anticancer drugs has yet to be defined.

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“…HER2 + BC can be treated with monoclonal antibodies against HER2, such as trastuzumab. TNBC does not express specific molecules; therefore, standard cytotoxic chemotherapy (doxorubicin, docetaxel, 5-fluorouracil, platinum drugs, and other agents in different combinations) remains the standard of care for patients with TNBC (Nøhr-Nielsen et al, 2020;Su et al, 2020;Pal and Rakshit, 2021;Shimanuki et al, 2021). However, regardless of the treatment strategy, the potential side effects, including lymphedema, weight reduction, pain, and chemotherapyinduced peripheral neuropathy, are significant (Binkley et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review

et al. 2022

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Breast cancer is one of the top-ranked malignant carcinomas associated with morbidity and mortality in women worldwide. Chemotherapy is one of the main approaches to breast cancer treatment. Breast cancer initially responds to traditional first- and second-line drugs (aromatase inhibitor, tamoxifen, and carboplatin), but eventually acquires resistance, and certain patients relapse within 5 years. Chemotherapeutic drugs also have obvious toxic effects. In recent years, natural products have been widely used in breast cancer research because of their low side effects, low toxicity, and good efficacy based on their multitarget therapy. Apoptosis, a programmed cell death, occurs as a normal and controlled process that promotes cell growth and death. Inducing apoptosis is an important strategy to control excessive breast cancer cell proliferation. Accumulating evidence has revealed that natural products become increasingly important in breast cancer treatment by suppressing cell apoptosis. In this study, we reviewed current studies on natural product–induced breast cancer cell apoptosis and summarized the proapoptosis mechanisms including mitochondrial, FasL/Fas, PI3K/AKT, reactive oxygen species, and mitogen-activated protein kinase–mediated pathway. We hope that our review can provide direction in the search for candidate drugs derived from natural products to treat breast cancer by promoting cell apoptosis.

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Pharmacodynamic modelling reveals synergistic interaction between docetaxel and SCO-101 in a docetaxel-resistant triple negative breast cancer cell line

Cited by 11 publications

References 19 publications

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

Oncogenic dysregulation of pre‐mRNA processing by protein kinases: challenges and therapeutic opportunities

Four phase 1 trials to evaluate the safety and pharmacokinetic profile of single and repeated dosing of SCO‐101 in adult male and female volunteers

Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review

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