Edy Meiyanto

N-Myc and c-Myc, as two major members of the MYC family proteins, independently contribute to hepatocellular carcinoma (HCC) by promoting proliferation, survival, and metabolic reprogramming. Overexpression of both proteins correlates with poor clinical outcomes, while intrinsic structural disorder hinder direct pharmacological targeting of MYC proteins. CCA-1.1 exhibits enhanced biological and physicochemical properties over its parent compound, curcumin, and demonstrates potent anti-cancer activity in various cancer types. We aim to investigate the anti-proliferative activity of CCA-1.1 through modulation of the MYC proteins and induction of cell cycle arrest and/or cell death mechanisms, including senescence, apoptosis, and autophagy. CCA-1.1 exhibited potent and irreversible anti-proliferative activity on Huh-6 cells by inhibiting EGFR kinase activity and its downstream signalling. CCA-1.1 also promoted G2/M arrest, induced apoptosis, and generated senescence. At the molecular level, CCA-1.1 downregulated N-Myc and c-Myc protein levels through the promotion of GSK3β activation and suppression of NCYM, a stabilizer protein of N-Myc. Furthermore, CCA-1.1 activated autophagy as a result of MYC protein destabilization. CCA-1.1 exerts a multi-faceted anti-cancer effect in MYCN-expressed HCC cells by inhibiting kinase signalling and destabilizing MYC proteins, leading to apoptosis, senescence, and autophagy. Molecular docking and molecular dynamic simulation revealed that CCA-1.1 interacted with both N-Myc and c-Myc. Our findings demonstrate CCA-1.1 as a distinctive anti-cancer candidate for HCC driven by MYC activation.

Combination therapy using natural-based substances is an effective approach to increase the efficacy of doxorubicin (Dox) while reducing its toxicity towards normal cells. This general chemotherapeutic agent treats various cancer cells, including triple-negative breast cancer (TNBC). Citrus sinensis peel extract (CPE) contains sinensetin (Sin), which exhibits anti-cancer effects, offering good prospects as a co-chemotherapy agent. This research aims to evaluate the co-chemotherapeutic potency of CPE-contained Sin when combined with Dox and also study its influence on 4T1 cell migration. Assays performed in this experiment included cell viability assay using MTT in individual and combination manner, clonogenic assay to analyse the proliferation inhibition effects of the treatments, scratch wound healing assay to assess the cells’ migration status, and gelatine zymography to evaluate cells’ matrix metalloproteinase-9 (MMP-9) activity.. This experiment confirmed that CPE and Sin had cytotoxic effects on 4T1 cells with the IC50 of 536 μg mL-1 and 120 μM, respectively, while Dox performed cytotoxicity on 4T1 cells with an IC50 of 2 μM. The combination of CPE and Dox showed strong synergistic effects with the combination index (CI) <1.0. CPE and its co-administration with Dox permanently suppressed the colony formation of 4T1 cells after 10 days of treatment removal. CPE and Sin inhibited the 4T1 cell migration strongly compared to Dox. CPE in its single and mixture form with Dox inhibited the MMP-9 activity. These results suggest that CPE, when combined with Dox, could be a promising co-chemotherapy regimen for TNBC treatment, potentially reducing the risk of metastasis and relapse.

Cancer is the most common cause of death, with the burden increasing in recent years. Conventional treatments have caused cancer cells’ resistance to drugs. Therefore, it is crucial to develop a radio-labeled theranostic compound such as penta-gamma-vunone (PGV), which significantly suppresses cancer cell growth. In this experiment, the synthesis of [131I]I-PGV-0 compound was done by using the standard Chloramine-T (CT) iodination method with some parameter optimizations, such as the quantity of CT oxidizer and sodium metabisulfite reducing agent, time and temperature of reaction. The radiochemical purity of these compounds was determined using thin layer chromatography (TLC) analysis, and the stability of the radiolabeled compound was also assessed in HBSS medium. Results showed that the highest radiochemical purity (RCP) of [131I]I-PGV-0 (99.83%) was obtained at the CT amount of 25 µg. Stability study revealed that, at the high RCP, this compound was stable for 16 days in cold storage. Molecular docking studies indicated that the radioiodination of PGV-0 enhances binding affinity by interacting with crucial amino acids within the kinase domains of EGFR, HER2, AURKA, and PLK-1.

Background: Non-steroidal anti-inflammatory drugs (NSAID) are widely used in temporomandibular joint osteoarthritis management. However, the side effects of NSAIDs on multiple organs need to be anticipated. Curcumin is known for its anti-inflammatory and analgesic potential, comparable to that of NSAIDs. In a previous study, structurally modified curcumin increased the pharmacological effect and simultaneously reduced the toxicity and side effects of curcumin. Pentagamavunon-0 (PGV-0) is one of the active components synthesized by the structure modification of curcumin. Purpose: In this study, we identify the potential target of PGV-0 on the pathogenesis of temporomandibular arthritis characterized by inflammation. Methods: We used a bioinformatics approach to compare the PGV-0 target with curcumin and diclofenac sodium as controls. We identified overlapping gene targets of bioactive compounds (PGV-0, curcumin, or diclofenac sodium) retrieved from the SwissTargetPrediction and GeneCards platforms, specifically for temporomandibular arthritis. An interaction model among targets was developed using the STRING database and Gene Ontology Panther to expound on the bioactive compound’s function on the key signaling pathway. Finally, we formulated a molecular docking prediction between the bioactive compound and the target protein marker derived from the previous analysis using Molecular Operating Environment tools. Results: This study found that curcumin and PGV-0 targeted different molecular pathways in temporomandibular arthritis compared to diclofenac sodium. Curcumin and PGV-0 shared a similar pathway to curcumin by modulating metalloproteinases (MMPs), especially MMP-9 and MMP-13. Moreover, diclofenac sodium influenced cyclooxygenase metabolism. Conclusion: In this study, PGV-0 targeted metalloproteinase in temporomandibular arthritis pathogenesis. This finding underlines the PGV-0 advantage in preventing metalloproteinase-related tissue damage in temporomandibular arthritis.

The use of radioactive isotopes in cancer treatment has marked a pivotal shift in modern medicine, where precise diagnosis and targeted therapy now blend to offer patients more effective care with minimized side effects. Despite significant advancements, the exploration of iodine-labeled radioligands from natural sources remains underdeveloped, and comprehensive evaluations of their design, pharmacokinetics, and clinical relevance are still lacking. This gap has created a pressing need for systematic studies that bridge natural product chemistry with radiopharmaceutical applications. Since the initial application of iodine-131 in thyroid treatments, radioisotopes such as iodine-125 and iodine-131 have gained prominence in oncology due to their dual functionality: they enable accurate imaging while delivering therapeutic radiation directly to tumor cells, reducing harm to surrounding healthy tissues. Recent advancements in radiopharmaceuticals, particularly iodine-labeled compounds, aim to further improve this balance by enhancing cancer treatment efficacy and safety. This review synthesizes findings from clinical and experimental studies that explore a range of iodine-labeled compounds, including natural agents like hypericin, curcumin, and piperine, as well as various synthetic analogs. Key methodologies for incorporating iodine, such as the Iodogen method and other stable-labeling techniques, are evaluated for their impact on the compounds’ pharmacokinetics, stability, and therapeutic performance. Furthermore, in silico methods are highlighted for their contribution to optimize the molecular structures, binding affinities, and specificity, streamlining the selection of high-potential candidates for radiopharmaceutical applications. Findings reveal that iodine-labeled compounds effectively concentrate in tumor cells, enhancing selectivity and reducing radiation exposure to non-cancerous tissues. Notably, these compounds demonstrate stability in biological environments, making them viable options for integrated diagnostic and therapeutic purposes. Moving forward, the ongoing refinement of compound stability and targeted biodistribution is crucial in ensuring these therapies can meet the demands of precision oncology and improve clinical outcomes across various cancer types.

Effect of PGV-1 on Apoptosis via Mitotic Arrest and Senescence in Polyploid Giant Cancer Cells of Hepatocellular Carcinoma JHH4 - Turkish Journal of Pharmaceutical Sciences

Neuroblastomas evade apoptosis due to oncogene mutations and antiapoptotic proteins, necessitating novel therapeutics that work in concert with other forms of cell death. Pyroptosis has potential as a strategic cell death mechanism in neuroblastoma. This study aimed to identify compounds that modulate pyroptosis, specifically those that target gasdermin D (GSDMD) oligomerization. The study employed computational analysis and in vitro screening. The COCONUT database provides the natural compound dataset. Drug-likeness analysis and pharmacophore fitting were applied to screen potential GSDMD oligomerization modulators. Hit compounds underwent molecular docking with MOE and molecular dynamic (MD) simulations with NAMD 2.14 to analyse structural changes. The computational screening results were corroborated by in vitro assays, including the WST-8 assay, Western blot, and immunofluorescence, which target pyroptosis-specific caspase-1. Pharmacophore fitting, molecular docking, and molecular dynamics simulations identified the top five compounds, namely, quercetin, naringenin, hesperetin, curcumin, and galangin, as potent modulators of GSDMD oligomerization. Among these compounds, curcumin, quercetin, and galangin exerted potent cytotoxic effects on GSDMD-expressing neuroblastoma SK-N-AS cells, with IC₅₀ values of 21, 37, and 49 µM, respectively. Curcumin and quercetin also promoted apoptosis via increased caspase-3 cleavage and reduced procaspase-7 and -8 levels, as shown by immunoblotting. Curcumin and galangin upregulated caspase-1 expression, as demonstrated by the detection of a fluorescent-labelled inhibitor of caspase-1 by immunostaining, suggesting that these two compounds could induce pyroptosis. Hesperetin and naringenin showed low cytotoxicity, had no effect on caspase activation, and did not exhibit signs of pyroptosis in SK-NA-S cells. Our study successfully identified curcumin as a strong regulator of both apoptosis and pyroptosis, quercetin as a strong modulator of apoptosis, and galangin as a strong modulator of pyroptosis. Further research on these compounds is crucial for the development of novel therapeutic strategies for neuroblastoma treatment.

Context: Breast cancer remains the second leading cause of cancer-related mortality worldwide, driven by uncontrolled cellular proliferation and metastasis. Natural radiopharmaceuticals have gained interest due to their potential for reduced side effects compared to synthetic agents. Among these, hesperidin and hesperetin, especially in iodinated forms, have emerged as promising therapeutic candidates targeting key breast cancer-related signaling pathways. Aims: To evaluate iodinated hesperidin derivatives as multi-target breast cancer therapeutics using molecular docking (AutoDock) and dynamics (GROMACS). Methods: Multi-target molecular docking and 100 ns molecular dynamics simulations were conducted to examine interactions with key breast cancer proteins: EGFR kinase, human estrogen receptor alpha (ER-α), and I-kappa-B-alpha/NF-kappa-B. Binding energies (∆G) were computed, and complex stability was assessed using RMSD, RMSF, and MM-PBSA analyses. Pharmacokinetic and toxicity properties were also predicted. Results: Docking results indicated strong affinities for iodinated derivatives (-6.14 to -7.51 kcal/mol), notably with EGFR and ER-α. Molecular dynamics simulations confirmed enhanced stability and reduced structural fluctuations in iodinated complexes. MM-PBSA calculations showed improved binding free energies, supporting increased interaction strength. Despite lower solubility, ADME predictions suggested favorable gastrointestinal absorption and drug-likeness for iodinated hesperetin. Toxicity analyses predicted moderate nephrotoxicity and cardiotoxicity risks, with lower LD50 values, indicating a need for dose optimization. Conclusions: Iodinated hesperidin and hesperetin exhibit stable binding interactions and favorable pharmacological profiles, highlighting their potential as novel radiopharmaceuticals in breast cancer therapy. These findings warrant further preclinical investigation and optimization for future drug development.

Context: The development of curcumin analog compounds containing boron as anticancer agents is ongoing. Diboronocurcumin analogs are promising for development as selective and targeted anti-breast cancer agents. We designed five novel diboronocurcumin analogs (CCB-4 to CCB-8) featuring heterocyclic ketones to address current limitations in breast cancer treatment, including resistance and toxicity. Aims: To identify potential targets and molecular pathways of diboronocurcumin analogs in breast cancer, utilizing a bioinformatics technique and structure-based in silico research. Methods: Target prediction was performed using databases including TargetNet, GeneCards, OMIM, and NCBI. Functional network analysis tools, such as STRING, Cytoscape, GO, and KEGG, were utilized to identify key signaling pathways in breast cancer. Molecular docking was employed to evaluate the binding interactions between diboronocurcumin analogs and the predicted target proteins. Results: ESR1, RELA, HDAC1, and MMP9 were four targets of diboronocurcumin analogs implicated in the processes of breast cancer cell proliferation, metastasis, and death, according to bioinformatics approaches. Molecular docking studies revealed that diboronocurcumin analogs had a high affinity for the four targets. CCB-4 to CCB-8 demonstrated stronger binding to ESR1 (-10.18, -10.49, -9.19, -10.24, and -10.85 kcal/mol, respectively) than tamoxifen (-9.52 kcal/mol). In addition, CCB-5 and CCB-8 exhibited greater binding to IKK (upstream pathway kinase of RELA), compared to doxorubicin, tamoxifen, and lapatinib. Conclusions: This study provides insights into the multi-target potential of diboronocurcumin analogs in suppressing breast cancer progression. Further in vitro and in vivo validation is supported by encouraging in silico results, particularly for CCB-5 and CCB-8.

Black seed (Nigella sativa L.) is well known for its pharmacological properties, particularly its anticancer activity, with previous studies demonstrating its cytotoxic effects on several cell lines, such as A‐549, DLD‐1, MDA‐MB231, or HCT. This study aims to investigate the effects of black seed oil (BSO) on the migratory activity of 4T1 triple‐negative breast cancer (TNBC) cells, focusing on its bioactive properties. BSO was extracted via hydro‐distillation and analyzed for its phytochemical composition using gas chromatography–mass spectrometry (GC‐MS). The cytotoxicity of BSO and doxorubicin (Dox) was assessed using the MTT assay. The effects of BSO and Dox on cell migration and matrix metalloproteinase‐9 (MMP‐9) expression were evaluated using a scratch wound‐healing assay and gelatin zymography method respectively. Additionally, intracellular reactive oxygen species (ROS) levels were measured using 2’,7’‐dichlorofluorescin diacetate (DCFDA) staining. GC‐MS analysis identified p‐cymene as a major component of BSO, along with various other bioactive compounds. BSO exhibited low toxicity toward 4T1 cells, while its combination with Dox reduced cell viability in a dose‐dependent manner. Furthermore, BSO in combination with Dox inhibited cell migration and suppressed MMP‐9 expressions in 4T1 cells. BSO treatment also led to an increase in ROS levels. In conclusion, BSO exhibits potential anticancer properties by inhibiting cell migration and downregulating MMP‐9 expression, highlighting its possible therapeutic role in TNBC treatment.