Revealing the Potency of Cinnamon as an Anti-cancer and Chemopreventive Agent

Cinnamon (Cinnamomum spp.), an ancient spice, has been explored as a potential for medicinal purposes. Despite numerous studies about its potency in overcoming of numerous diseases, the potency as anti-cancer would be a challenge. This current article provides a review of the anti-cancer and chemoprevention potency of cinnamon and its major constituents: cinnamaldehyde, cinnamic acid, 2-hydroxycinnamaldehyde, 2-methoxycinnamaldehyde, and eugenol. Comprehensively, cinnamon and its constituents exhibit the anti-cancer and cancer prevention activities through various mechanisms: (1) anti-proliferation, (2) induction of cell death, (3) anti-angiogenesis, (4) anti-metastasis, (5) suppression of tumor-promoted inflammation, (6) immunomodulation, and (7) modulation of redox homeostasis; both in vitro and in vivo. Moreover, cinnamon also shows the synergistic anti-cancer effect with well-known anti-cancer drugs, such as doxorubicin, which support its potency to be used as a combination chemotherapeutic (co-chemotherapeutic) agent. However, further study should be established to determine the exact target molecule(s) of cinnamon in the cancer cells.Keywords: cinnamon, spice, cancer, anti-cancer, chemopreventiv

Synergistic Effect of Cinnamon Essential Oil (Cinnamomum burmannii) and Doxorubicin on T47D Cells Correlated with Apoptosis Induction

Cinnamon  (Cinnamomum burmannii)  shows  anticancer activity  in  several  types  of  cancer  cells.  The aim of this study is to  observe the  cytotoxic  activity  of  cinnamon essential oil (CEO) solely and its combination with doxorubicin,  also the  ability  of  the  combination to induce apoptosis on T47D breast cancer cells. The CEO was prepared through distillation of dry cinnamon bark. Cytotoxic  assay  was performed by using MTT assay and apoptosis determination was done by using double staining with ethidium bromide and acridine orange. The result showed that CEO exhibited cytotoxic effect on T47D cells with IC50 values of 75 µg/ml.  Moreover, CEO showed synergist effect with doxorubicin. The lowest combination index (CI) with CI values of 0,37 was obtained by combination of doxorubicin-CEO  37,5  µg/ml-1,25  µM.  Treatment with CEO solely and its combination with doxorubicin showed apoptosis induction on T47D cells. The results of this  study  indicate  the potency of CEO  to  be  developed  as co-chemotherapeutic  agent  of  doxorubicin on breast cancer. Keywords:  cinnamon essential oil, doxorubicin, T47D cells, combination cytotoxi

Personalized Drug Discoveries for Patients with GNAO1 Encephalopathies

GNAO1 encephalopathy is a group of neurodevelopmental disorders caused by mutations in the GNAO1 gene encoding the major neuronal G protein, Gαo. Patients with this disease suffer from a broad range of symptoms, including epilepsy, movement disorders, hypotonia, and developmental delay. Unfortunately, a large subset of patients are refractory to available medications for epilepsy and movement disorders. This thesis work is part of the basic and translational projects that aim to understand the molecular defects of pathogenic Gαo, followed by personalized drug discovery based on the specific biological properties of the variant. More than 80 pathogenic variants of Gαo have been identified, and in this study, we focus on four most recurrent variants: G203R, R209C, E246K, and T241_N242insPQ. Using in vitro biochemical assay, cellular assay, and molecular modeling, we unraveled the molecular defects of these pathogenic Gαo. These understanding then led us to develop a personalized drug discovery pipeline for different pathogenic Gαo. High-throughput screening (HTS) assays were performed to find small molecules that might, at least partially, correct the defect of the mutant Gαo. Hits validated in vitro and in cellular assays were then validated in vivo in the animal model of GNAO1 encephalopathy. Overall, our works have pioneered a personalized drug discovery approach for GNAO1 encephalopathy. </p

Unlocking the Wnt pathway: therapeutic potential of selective targeting FZD7 in cancer

The Wnt signaling is of paramount pathophysiological importance. Despite showing promising anticancer activities in pre-clinical studies, current Wnt pathway inhibitors face complications in clinical trials resulting from on-target toxicity. Hence, the targeting of pathway component(s) that are essential for cancer but dispensable for normal physiology is key to the development of a safe Wnt signaling inhibitor. Frizzled7 (FZD7) is a Wnt pathway receptor that is redundant in healthy tissues but crucial in various cancers. FZD7 modulates diverse aspects of carcinogenesis, including cancer growth, metastasis, maintenance of cancer stem cells, and chemoresistance. In this review, we describe state-of-the-art knowledge of the functions of FZD7 in carcinogenesis and adult tissue homeostasis. Next, we overview the development of small molecules and biomolecules that target FZD7. Finally, we discuss challenges and possibilities in developing FZD7-selective antagonists

GNAO1 Mutations Affecting the N‐Terminal α‐Helix of Gαo Lead to Parkinsonism

Background Patients carrying pathogenic variants in GNAO1 present a phenotypic spectrum ranging from severe early‐onset epileptic encephalopathy and developmental delay to mild adolescent/adult‐onset dystonia. Genotype–phenotype correlation and molecular mechanisms underlying the disease remain understudied. Methods We analyzed the clinical course of a child carrying the novel GNAO1 mutation c.38T&gt;C;p.Leu13Pro, and structural, biochemical, and cellular properties of the corresponding mutant Gαo— GNAO1 ‐encoded protein—alongside the related mutation c.68T&gt;C;p.Leu23Pro. Results The main clinical feature was parkinsonism with bradykinesia and rigidity, unlike the hyperkinetic movement disorder commonly associated with GNAO1 mutations. The Leu ➔ Pro substitutions have no impact on enzymatic activity or overall folding of Gαo but uniquely destabilize the N‐terminal α‐helix, blocking formation of the heterotrimeric G‐protein and disabling activation by G‐protein‐coupled receptors. Conclusions Our study defines a parkinsonism phenotype within the spectrum of GNAO1 disorders and suggests a genotype–phenotype correlation by GNAO1 mutations targeting the N‐terminal α‐helix of Gαo.</p

Restoration of the GTPase activity and cellular interactions of Gαo mutants by Zn2+ in GNAO1 encephalopathy models

De novo point mutations inGNAO1, gene encoding the major neuronal G protein Gαo, have recently emerged in patients with pediatric encephalopathy having motor, developmental, and epileptic dysfunctions. Half of clinical cases affect codons Gly203, Arg209, or Glu246; we show that these mutations accelerate GTP uptake and inactivate GTP hydrolysis through displacement Gln205critical for GTP hydrolysis, resulting in constitutive GTP binding by Gαo. However, the mutants fail to adopt the activated conformation and display aberrant interactions with signaling partners. Through high-throughput screening of approved drugs, we identify zinc pyrithione and Zn2+as agents restoring active conformation, GTPase activity, and cellular interactions of the encephalopathy mutants, with negligible effects on wild-type Gαo. We describe aDrosophilamodel ofGNAO1encephalopathy where dietary zinc restores the motor function and longevity of the mutant flies. Zinc supplements are approved for diverse human neurological conditions. Our work provides insights into the molecular etiology ofGNAO1encephalopathy and defines a potential therapy for the patients

Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth

Abstract Curcumin has been reported to exhibit anti-tumorigenic activity; however, since its precise actions remain unclear, its effects are considered to be deceptive. In the present study, we confirmed the anti-tumorigenic effects of curcumin on CML-derived leukemic cells in a xenograft model and in vitro culture system. In vitro pull-down and mass analyses revealed a series of enzymes (carbonyl reductase, glutathione-S-transferase, glyoxalase, etc.) that function in a reactive oxygen species (ROS) metabolic pathway as curcumin-binding targets, the expression of which was up-regulated in human leukemia. Curcumin increased ROS levels over the threshold in leukemic cells, and the antioxidant, glutathione (GSH) and overexpression of curcumin-binding enzymes partially mitigated the up-regulation of ROS and growth inhibition caused by curcumin. These results show that curcumin specifically inhibits tumor growth by increasing ROS levels over the threshold through the miscellaneous inhibition of ROS metabolic enzymes. Curcumin has potential in therapy to regulate ROS levels in tumor cells, thereby controlling tumor growth