quinacrine (CBL0102) / Incuron - LARVOL DELTA

Targeting histone chaperone FACT complex sensitizes medulloblastoma cells to chemo and radiation therapy (AACR 2018) - "Of importance, downregulation of APE1 levels or inhibition of FACT with CBL0137/curaxin sensitizes a panel of highly aggressive MB cell lines to cisplatin and alkylating drug temozolomide.Together, our study suggest that co-suppression of both BER and NER pathways via targeting FACT complex can greatly sensitize MB tumors to chemo and radiation therapy. A major implication of our studies is that combination of curaxin with low dose of cisplatin may have considerable therapeutic potential to improve efficacy and reduce cytotoxic side effects of cisplatin to MB patients."

Neuroendocrine Tumor

Targeting histone chaperone FACT complex and APE1 sensitizes colon cancer cells to chemotherapy (AACR 2018) - "In nude mice xenograft, combination of curaxin and 5-FU group slowed the growth of tumor to the largest extent as compared to 5-FU and curaxin groups. Interruption of APE1 and FACT interaction exhibits synergistic effect on cell viability and proliferation upon DNA damage with chemotherapeutic drugs. We demonstrate targeting both FACT and BER pathway together as a novel strategy for chemosensitization of colon cancer cells."

Colorectal Cancer

The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic pontine glioma tumor cells (AACR 2018) - "Our data suggests that minor groove binding agents like quinacrine could be effective therapies for this lethal brain tumor. Our future studies are aimed at testing the efficacy of quinacrine in inhibiting DIPG tumorigenicity and elucidating the mechanism of action."

Solid Tumor

Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine (AACR 2018) - "Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for AT/RT. Future studies are aimed at testing the in vivo efficacy and validating the mechanism of action of quinacrine in AT/RT."

Clinical • PARP Biomarker • Solid Tumor

Quinacrine-mediated activation of JNK1 inhibits Nrf2 and causes cell death in human colon cancer (AACR 2018) - "Finally, the quinacrine-mediated degradation of Nrf2 was found to increase the sensitivity of colorectal cancer in in vivo model and cancer cells under both normoxia and hypoxia in vitro to ROS-inducing drugs and anticancer drugs commonly used against colorectal cancer. Quinacrine caused colorectal cancer cell death by promoting activation of JNK1-mediated Nrf2 degradation."

IO Biomarker • Colorectal Cancer

Characterization of Platelet Function with Flow Cytometry for Bleeding Risk Evaluation in Hematological Disorders (ISTH-SSC 2018) - "Levels of CD42b, CD61, CD62P, PAC1, annexin V binding, and mepacrine release were determined. Pediatric patients hemorrhagic syndrome of unclear origin and excluded coagulopathy (n=32), preterm neonates (33-34 gestation weeks, n=10) and term neonates (>37 gestation weeks, n=10), pediatric (n=44) and adult (n=32) patients with chronic immune thrombocytopenia (ITP) and adult patients with chronic lymphocytic leukaemia (CLL, n=17) before and on ibrutinib treatment were analysed. Functional platelet flow cytometry parameters correllate with bleeding risk in hematological disorders and other acquired platelet dysfunction conditions."

Biosimilar • Chronic Lymphocytic Leukemia • Hemophilia • Immunology • Indolent Lymphoma • Venous Thromboembolism

A combination of suberoylanilide hydroxamic acid and quinacrine is an effective therapeutic approach in preclinical settings of upper gastrointestinal cancers (AACR 2017) - "Our novel findings show that QC and SAHA have a synergistic effect on cancer cell death. The results provide compelling evidence that increased DNA damage mediates the cytotoxic effect of combined QC/SAHA. Such effect is likely related to mutP53 and wtP53 protein degradation induced by QC/SAHA combination."

Combination therapy • Biosimilar • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology

Alterations in the parameters of classic, global, and innovative assays of hemostasis caused by sample transportation via pneumatic tube system. (PubMed, Thromb Res) - "Transportation by PTS caused significant shifts in parameters of functional and integral assays that exceeded parameter variation values and sometimes even were comparable to normal ranges. The results obtained in this study indicate that using of PTS for such assays may cause sufficient alterations of results and can lead to patient's mistreatment. "

Clinical • Journal • Biosimilar

FACT is a sensor of DNA torsional stress in eukaryotic cells. (PubMed, Nucleic Acids Res) - "...We found that the binding of candidate anticancer drug, curaxin, to cellular DNA results in uncoiling of nucleosomal DNA, accumulation of negative supercoiling and conversion of multiple regions of genomic DNA into left-handed Z-form...Thus, we propose that FACT acts as a sensor of ADS formation in cells. Recognition of ADS by FACT followed by a p53 response may explain the role of FACT in DNA damage prevention."

Journal • Biosimilar • Oncology

5-hydroxytryptamine has an endothelium-derived hyperpolarizing factor-like effect on coronary flow in isolated rat hearts. (PubMed) - "In the present study, we found that 5-HT-induced coronary flow increases are mediated by the activation of 5-HT7 receptor in rat hearts in the absence of L-NAME. Metabolites of cytochrome P450s, small-conductance Ca(2+)-activated K(+) channel, and intermediate-conductance Ca(2+)-activated K(+) channel are involved in 5-HT-induced coronary flow increases in L-NAME-treated hearts, which resemble the mechanisms of EDHF-induced vasorelaxation. The role of large-conductance Ca(2+)-activated K(+) channel in 5-HT-induced coronary flow increases in L-NAME-treated hearts needs further investigation."

Journal • Biosimilar

Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus. (PubMed, J Investig Dermatol Symp Proc) - "Although hydroxychloroquine (HCQ) is frequently used, addition of quinacrine (QC) has shown additional clinical effects when combined with HCQ. Flow cytometry showed that QC significantly suppressed intracellular expression of TNF-α from the lipopolysaccharide-stimulated myeloid dendritic cells and monocytes of DM patients (P-values ≤ 0.0008). In conclusion, QC likely has a different mechanism of action than HCQ, given the broader inhibition of proinflammatory cytokines, including both TNF-α and IFN-α."

Journal • Review • Biosimilar • Immunology • Inflammation • Lupus • Myositis

Screening of FDA approved drugs for their ability to inhibit or worsen hydrogen peroxide mediated aggregation of calf lens crystallins (ARVO 2018) - "...Among those that worsened transparency are amiodarone, quinacrine and thiothixene...Surprisingly, hydrocortisone, a known risk factor for cataract, improved aggregation possibly by acting like a sterol or antioxidant...We have screened a small molecule compound library of FDA approved drugs for their ability to prevent or worsen oxidative damage to lens proteins. Candidate compounds discovered so far will be tested in an animal model for their ability to prevent or induce cataract, respectively."

Biosimilar • Ophthalmology

"Salviamo mio figlio, approviamo il farmaco curaxin 137 @Aifa_ufficiale @EMA_News @BeaLorenzin - Firma la petizione! https://t.co/SGwMp8qj2l via @ChangeItalia" (@ElioFerrari3)

ERG2 and ERG24 are required for normal vacuolar physiology as well as Candida albicans pathogenicity in a murine model of disseminated but not vaginal candidiasis. (PubMed) - "Thus while targeting Erg2p or Erg24p alone could provide a potentially efficacious therapy for disseminated candidiasis, it may not be an effective strategy to treat vaginal infections. The potential value of drugs targeting these enzymes as adjunctive therapies is discussed."

Journal • Biosimilar • Immunology

Fluorescence chromosome banding and FISH mapping in perennial ryegrass, Lolium perenne L. (PubMed) - "By enabling the allocation of genes mapped by other methods to physically identified chromosome positions, this work will contribute to a better understanding of genomic structures and functions in grasses."

Journal • Biosimilar

Therapeutic Effect of Quinacrine, an Anti-protozoan Drug, by Selective Suppression of p-CHK1/2 in p53-negative Malignant Cancers. (PubMed, Mol Cancer Res) - "Quinacrine has been used for the past over 70 years without obvious side-effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies."

Journal • Biosimilar • Breast Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Kinetic Application of Flow Cytometry for Patients with Unknown Bleeding Disorders: The Underestimated Value of Mepacrine (ISTH-SSC 2018) - "We established an easy, quick and inexpensive assay as an additional diagnostic module in flow cytometry-based platelet function tests."

Clinical • Biosimilar • Genetic Disorders • Hematological Malignancies • Hemophilia • Immunology • Oncology • Primary Immunodeficiency

The coagulation state of patients with infective endocarditis (HEART FAILURE 2018) - "...In patients there was a significant decrease in mepacrine uptake in dense granules before activation: median value 70 vs 100 (p<0.001) in healthy individuals... Platelets functional activity in IE patients was mostly increased before activation and decreased after. Plasma coagulation reveal hypercoagulation in patients with IE via thrombodymanics."

Clinical • Biosimilar • Cardiovascular • Heart Failure • Immunology • Venous Thromboembolism

Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and chemotherapeutic agents (Cancer Biol Ther) - Quinacrine at concentrations of 10-20 mM for 1-2 d cannot kill HCC cells but it renders these cells sensitive to treatment by TRAIL; Co-treatment of these cells with quinacrine & TRAIL induces overwhelming cell death within 3-4 hrs; Quinacrine synergizes with chemotherapeutics, such as adriamycin, 5-FU, etoposide, CPT11, sorafenib, and gemcitabine, in killing hepatocellular carcinoma cells in vitro and the drug enhances the activity of sorafenib to delay tumor growth in vivo

None • Oncology

Cleveland BioLabs: Annual Report 2013 (Cleveland BioLabs) - Anticipated patent expiry in US on method of use for liver cancer in 2025; Anticipated expiry of pending patent applications between 2024-2035 

Anticipated patent expiry • Oncology

Heart Failure Risk Among Patients with Rheumatoid Arthritis: Association with Anti-Rheumatic Drugs (ACR-ARHP 2018) - "Medication categories were: non-biologic disease modifying anti-rheumatic drug (DMARD) [azathioprine, cyclophosphamide, leflunomide, methotrexate, sulfasalazine]; anti-tumor necrosis factor (TNF) [adalimumab, certolizumab, etanercept, golimumab, infliximab]; antimalarial [chloroquine, hydroxychloroquine, quinacrine]; other biologic/small molecule DMARD [abatacept, anakinra, rituximab, tocilizumab, tofacitinib]; and systemic corticosteroid. RA patients are at risk for HF. Established cardiovascular disease or traditional risk markers are associated with increased risk. Anti-rheumatic medications variably associate with HF risk, with lower risk observed among patients taking non-biologic or other biologic/small molecule DMARDs or systemic corticosteroids."

Clinical

Baseline Features and Outcomes of Pediatric-Onset Discoid Lupus Erythematosus: Interim Data Analysis of a Multicenter Retrospective Cohort Study (ACR-ARHP 2018) - "This study represents the largest investigation of pediatric DLE performed to date. Utilizing both ACR and SLICC classification criteria for SLE, most patients (>73%) presented with skin-limited DLE, with a low cumulative incidence of SLE using both ACR and SLICC classification criteria. Further analysis may help to determine risk factors for progression to SLE and inform the creation of consensus guidelines for treating children with DLE."

Retrospective data

Platelet's disorder in a case of chronic lymphocytic leukemia (LLC) (EAHAD 2018) - "...He started therapy with bendamustine 90mg/m2 (3 cycles) and rituximab 375mg/m2/28days (6 cycles) for the hematological malignancy and he was also treated with antifibrinolytic tranexamic acid (1g/daily) to prevent other bleedings...Delta-granules were studied by uptake and release of mepacrine by flow cytometry... Our analysis confirmed the clinical suspicion of a platelets disorder, as -storage pool, related to LLC in a patient with several spontaneous cerebral hemorrhages. We documented an improvement in platelet function associated to an apparently clinical resolution of bleeding diathesis, subsequent to the treatment of the hematological malignancy. We intend to confirm these data at the end of treatment and after a longer follow-up."

Clinical