CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a timedependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl- Stat5 related malignancies.This research has been supported by the Spanish Ministry of Science and Innovation (SAF2009-13296) and MINECO (SAF2012-37344, SAF2014-53526R, and SAF2015-65113-C2-2-R) with the co-funding of European Regional Development Fund (ERDF). This Project has been also supported by Centro Atlántico del Medicamento S.A. (CEAMED; www.ceamedsa.com) and Alfredo Martín-Reyes Foundation (Arehucas)-Canary Islands Foundation for Cancer Research (FICIC).Peer Reviewe

Chemical-proteomics Identify Peroxiredoxin-1 as an Actionable Target in Triple-negative Breast Cancer

Triple-negative breast cancer (TNBC) is difficult to treat; therefore, the development of drugs directed against its oncogenic vulnerabilities is a desirable goal. Herein, we report the antitumor effects of CM728, a novel quinone-fused oxazepine, against this malignancy. CM728 potently inhibited TNBC cell viability and decreased the growth of MDA-MB-231-induced orthotopic tumors. Furthermore, CM728 exerted a strong synergistic antiproliferative effect with docetaxel in vitro and this combination was more effective than the individual treatments in vivo. Chemical proteomic approaches revealed that CM728 bound to peroxiredoxin-1 (Prdx1), thereby inducing its oxidation. Molecular docking corroborated these findings. CM728 induced oxidative stress and a multi-signal response, including JNK/p38 MAPK activation and STAT3 inhibition. Interestingly, Prdx1 downregulation mimicked these effects. Finally, CM728 led to DNA damage, cell cycle blockage at the S and G2/M phases, and the activation of caspase-dependent apoptosis. Taken together, our results identify a novel compound with antitumoral properties against TNBC. In addition, we describe the mechanism of action of this drug and provide a rationale for the use of Prdx1 inhibitors, such as CM728, alone or in combination with other drugs, for the treatment of TNBC.This project was supported by Centro Atlántico del Medicamento S.A. (CEAMED), CDTI [IDI-20111517], ACIISI [EATIC2017010006], Universidad de Las Palmas de Gran Canaria, Cabildo Insular de Gran Canaria, Fundación del Instituto Canario de Investigación del Cáncer (FICIC), and Miguel Ángel Rodríguez Cardenes. E. Spínola-Lasso is the recipient of a predoctoral fellowship from the Agencia Canaria de Investigación, Innovación y Sociedad de la Información de la Consejería de Economía, Conocimiento y Empleo y por el Fondo Social Europeo (FSE) Programa Operativo Integrado de Canarias 2014-2020, Eje 3 Tema Prioritario 74 (85%) [TESIS2020010081]. J.C. Montero was funded by the Instituto de Salud Carlos III through the Miguel Servet Program [CP12/03073 and CPII17/00015] and received research support from the same institution [PI15/00684 and PI18/00796]. A. Pandiella received funding from the Ministry of Economy and Competitiveness of Spain [BFU2015-71371-R and PID2020-115605RB-I00], Instituto de Salud Carlos III through CIBERONC, Junta de Castilla y León [CSI146P20], CRIS Cancer Foundation, ACMUMA, UCCTA, ALMOM, and the European Community through the Regional Development Funding Program (FEDER)

Bone Mass and the CAG and GGN Androgen Receptor Polymorphisms in Young Men

BACKGROUND: To determine whether androgen receptor (AR) CAG (polyglutamine) and GGN (polyglycine) polymorphisms influence bone mineral density (BMD), osteocalcin and free serum testosterone concentration in young men. METHODOLOGY/PRINCIPAL FINDINGS: Whole body, lumbar spine and femoral bone mineral content (BMC) and BMD, Dual X-ray Absorptiometry (DXA), AR repeat polymorphisms (PCR), osteocalcin and free testosterone (ELISA) were determined in 282 healthy men (28.6+/-7.6 years). Individuals were grouped as CAG short (CAG(S)) if harboring repeat lengths of < or = 21 or CAG long (CAG(L)) if CAG > 21, and GGN was considered short (GGN(S)) or long (GGN(L)) if GGN < or = 23 or > 23. There was an inverse association between logarithm of CAG and GGN length and Ward's Triangle BMC (r = -0.15 and -0.15, P<0.05, age and height adjusted). No associations between CAG or GGN repeat length and regional BMC or BMD were observed after adjusting for age. Whole body and regional BMC and BMD values were similar in men harboring CAG(S), CAG(L), GGN(S) or GGN(L) AR repeat polymorphisms. Men harboring the combination CAG(L)+GGN(L) had 6.3 and 4.4% higher lumbar spine BMC and BMD than men with the haplotype CAG(S)+GGN(S) (both P<0.05). Femoral neck BMD was 4.8% higher in the CAG(S)+GGN(S) compared with the CAG(L)+GGN(S) men (P<0.05). CAG(S), CAG(L), GGN(S), GGN(L) men had similar osteocalcin concentration as well as the four CAG-GGN haplotypes studied. CONCLUSION: AR polymorphisms have an influence on BMC and BMD in healthy adult humans, which cannot be explained through effects in osteoblastic activity

Bone mineral content (BMC) and areal bone mineral density (BMD) of the upper and lower extremities.

<p>Subjects were grouped as CAG short (CAG_S) if harboring repeat lengths of ≤21 and CAG long (CAG_L) if harboring repeat lengths of >21. The cutoff point for GGN short (GGN_S) was GGN repeat polymorphism ≤23, otherwise subjects were included in the GGN long (GGN_L) group. Four haplotypes combinations were defined as: CAG_L + GGN_L, CAG_S + GGN_S, CAG_S + GGN_L, and CAG_L + GGN_S. * P<0.05 compared to CAG_S + GGN_S; $ P<0.05 compared to CAG_L + GGN_L.</p

Hip bone mineral content (BMC) and bone mineral areal density (BMD).

<p>Subjects were grouped as CAG short (CAG_s) if harboring repeat lengths of ≤21 and CAG long (CAG_L) if harboring repeat lengths of >21. The cutoff point for GGN short (GGN_s) was GGN repeat polymorphism ≤23, otherwise subjects were included in the GGN long (GGN_L) group. Four haplotypes combinations were defined as: CAG_L + GGN_L, CAG_S + GGN_S, CAG_S + GGN_L, and CAG_L + GGN_S. * P<0.05 compared to CAG_S + GGN_S; § P<0.05 compared to CAG_L + GGN_S.</p

Body composition, anthropometrics and physical activity in men with CAG_S and CAG_L androgen receptor polymorphisms (mean ± standard deviation).

<p>BMC: bone mineral content, BMD: bone mineral density. Individuals were considered as CAG short (CAG_S) if harboring repeat lengths ≤21 and CAG long (CAG_L) if harboring repeat lengths of >21.</p

Mean lumbar spine (from L₂, L₃ and L₄) bone mineral content (BMC) and bone mineral areal density (BMD).

<p>Subjects were grouped as CAG short (CAG_S) if harboring repeat lengths of ≤21 and CAG long (CAG_L) if harboring repeat lengths of >21. The cutoff point for GGN short (GGN_S) was GGN repeat polymorphism ≤23, otherwise subjects were included in the GGN long (GGN_L) group. Four haplotypes combinations were defined as: CAG_L + GGN_L, CAG_S + GGN_S, CAG_S + GGN_L, and CAG_L + GGN_S. * P<0.05 compared to CAG_S + GGN_S; § P<0.05 compared to CAG_L + GGN_S</p