Marwan Emara

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. Necrosis, and by inference hypoxia, is a pathognomonic feature of GBM tumors, where hypoxia significantly contributes to chemoresistance, leading to local treatment failure and disease progression. Although temozolomide (TMZ) is the main treatment option, 60–75% of GBM patients do not benefit from it. This study aimed to evaluate the therapeutic potential of Tetrandrine (TET) in combination with or compared to TMZ in treating GBM cells (M010b and U87) under both normoxic and hypoxic conditions. The therapeutic potential was assessed using qRT-PCR, MTT assay, combination index analysis, flow cytometry for apoptosis and cell cycle analysis, scratch assay, gelatin zymography, measurement of mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) production, and molecular docking. Under both normoxic and hypoxic conditions, TET showed significant cytotoxicity in both cell lines compared to TMZ. A synergistic effect was observed only under normoxia at 2× IC₅₀ concentrations in M010b cells, and at 4× IC₅₀ concentrations in U87 cells. TET significantly increased the sub-G1 cell population and apoptosis compared to TMZ in both cell lines under normoxic and hypoxic conditions, while TMZ induced G2/M arrest in U87 cells under both conditions. TET significantly increased ROS production in both cell lines under normoxia. Under both conditions, ΔΨm was significantly reduced by TET in M010b cells and by TMZ in both cell lines. TET and TMZ significantly reduced pro-MMP-2 levels in M010b cells under both conditions and in U87 cells under normoxia. In conclusion, given the limited therapeutic potential of TMZ, our findings suggest that TET could be a viable alternative treatment option for GBM.

A new series of thiazolo[4,5-d]pyrimidine derivatives was rationally designed and synthesized as dual PI3K/CDK6 inhibitors to concurrently target key oncogenic pathways via isoform selectivity. Structural optimization at C5 and C7 positions was explored to enhance interactions within the PI3K ATP-binding site and CDK6 hinge region. The new compounds showed significant cytotoxicity against colorectal (HCT 116), lung (A549), hepatocellular (SNU-449), and breast (MCF7) cancer cell lines, with minimal effects on normal human lung fibroblasts (CCD-16Lu). Compound 8b demonstrated balanced low-micromolar potency across multiple cell lines with IC50 range of 5.94-31.73 μM, and superior overall efficacy compared to its analogue 5b. SAR analysis showed that p-methoxyphenyl substitution improved both potency and spectrum, whereas m-substitution enhanced HCT 116 selectivity. Enzymatic assays confirmed dual PI3K/CDK6 inhibition, supported by cell cycle arrest, apoptosis induction, and molecular docking studies. These findings identify 8b as a promising candidate for dual kinase-targeted anticancer therapy.

Chalcone compounds have demonstrated potent anticancer activities in the past few decades with few adverse consequences. Using Claisen–Schmidt condensation, two new series of bis-chalcone derivatives (5a–c and 9a–c) bearing the thiophene moiety have been designed and generated. All compound structures were examined and elucidated by spectroscopic investigations. The MTT assay, gene expression assay, cell cycle analysis, apoptosis assay, Western blotting analysis, zymographic analysis, and molecular docking were used to evaluate the anticancer efficacy of the synthesized compounds against breast, colon, and lung cancer cells. Out of the two synthesized series, four compounds (5a, 5b, 9a, and 9b) showed significant cytotoxic effects against breast (IC₅₀ values of 7.87 ± 2.54 and 4.05 ± 0.96 μM for compounds 5a and 5b, respectively), colon (IC₅₀ values of 18.10 ± 2.51 and 17.14 ± 0.66 μM for compounds 5a and 9a, respectively), and lung (IC₅₀ values of 41.99 ± 7.64 and 92.42 ± 30.91 μM for compounds 5a and 9b, respectively) cancer. These compounds upregulated the proapoptotic genes and caspase-3 and -9 protein, downregulated antiapoptotic and matrix metalloproteinase 2 (MMP-2) gene, and MMP-2 and -9 enzymatic activity. Additionally, these compounds significantly increased early and late apoptosis, necrosis, and induced cell cycle arrest at the subG1 phase with a concomitant decrease in the percentage of cell fractions at G0/G1, S, and G2/M phases. Moreover, the molecular docking was carried out on caspase-3 and -9 and MMP-2 and -9. The results suggest that compounds 5a, 5b, 9a, and 9b are potential and effective anticancer drugs.

Colorectal cancer (CRC) is the third most common malignancy worldwide. 5-fluorouracil (5-FU) remains the first-line drug for treatment of the metastatic stage despite the limits of its efficacy. Here, we investigated the anti-tumor effect of two phytochemicals, baicalein and 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC), on colorectal cancer cells (HCT-116 and RKO) and determined whether these individual agents, when used alone or in combination with 5-FU, could enhance treatment efficacy. The evaluations included assays that measure cell viability and proliferation (MTT), apoptosis, cell migration, cell cycle, gelatin zymography, and combination index analyses. In both cell lines, baicalein [HCT-116 cells; IC50 = 40.82 ± 7.77 μM (24 h) and 33.83 ± 1.99 μM (48 h), and RKO cells; IC50 = 55.84 ± 3.12 μM (24 h) and 45.11 ± 3.05 μM (48 h)] and 6-MITC [HCT-116 cells; IC50 = 24.66 ± 1.57 μM (24 h) and 8.28 ± 0.56 μM (48 h), and RKO cells; IC50 = 45.74 ± 1.63 μM (24 h) and 9.85 ± 1.42 (48 h) μM] suppressed cancer cell proliferation in a dose-dependent manner at 24 and 48 h, while 5-FU was cytotoxic only after 48 h [HCT-116 cells; IC50 18.43 ± 3.82, and RKO cells; IC50 = 30.57 ± 8.34 μM]. Compared with 5-FU treatment only, the combined treatments induced significant increases in the pre-G1 phase and decreases in the G1 and S phases in both cell lines. In HCT-116 cells, combined treatments induced significantly greater apoptosis compared to 5-FU alone. Single and combination treatments with baicalein or 6-MITC significantly lowered the migration of cells compared to 5-FU alone in both cell lines. In conclusion, our study showed that both baicalein and 6-MITC induced similar anti-tumor effects compared to 5-FU alone in both cell lines, however, the combined treatments were more efficient.

Nalbuphine is associated with a significant risk of respiratory depression. Its central nervous system entry is hindered by P-glycoproteins, and lower P-glycoprotein activity is a risk factor for respiratory depression. We assessed the effect of hyperlipidemia on nalbuphine pharmacokinetics, brain and liver uptake, and analgesic response following single (2.5 mg/kg) and multiple (2.5 mg/kg/day for three days) doses in normolipidemic and hyperlipidemic rats. Trends of reduction and increase in nalbuphine C_max and Vd_ss/F were observed, respectively, in hyperlipidemic rats. Negative correlations were observed between C_max and serum lipoproteins. Serum-normalized brain and liver levels at 1 h post-dose were lower in hyperlipidemic rats, with brain and liver levels being negatively and positively correlated with TG and HDL, respectively. At steady state, marked nalbuphine accumulation was observed in hyperlipidemic rat brains (R = 1.6) compared with normolipidemic rats (R = 1.1). Nalbuphine analgesic response was not altered by hyperlipidemia at steady state. Caution should be exercised since greater brain accumulation in hyperlipidemic patients treated with nalbuphine could increase their risk of respiratory depression. Our study highlights an unexpected role of lipoproteins in drug absorption and tissue uptake. We also propose a model for reduced nalbuphine absorption based on interaction with intestinal HDL-3.

Since the development of cold atmospheric plasma (CAP), substantial and significant usage of CAP applications was introduced in medicine. Here, we developed two combined sources of plasma to produce in situ plasma‐activated air‐driven water mist (PAAWM). The first is generated using air as a feed gas, while the second is plasma‐activated water generated by the ignition of plasma within the air‐driven water mist. Both contribute to the plasma jet generation of PAAWM. The antitumor efficacy of PAAWM was evaluated against two hepatocellular carcinoma cell lines (SNU‐449 and SNU‐475). The generated PAAWM was efficient in the treatment of both chemosensitive and chemoresistant hepatocellular carcinoma cells. These results may support using PAAWM alone or in combination with other treatment modalities.

Immunotherapy has been established as a promising therapy for different cancer types. However, many patients experience primary or secondary resistance to treatment. Immune cells and anti-inflammatory factors are regulated by long noncoding RNAs (lncRNAs). In addition, lncRNAs have a role in immune resistance through antigen presentation loss or attenuation, PD-L1 upregulation, loss of T-cell activities, and activation of G-MDSCs and Tregs in the tumor environment. LncRNAs can also influence the interaction between cancer stem cells and immune cells in the tumor microenvironment, potentially resulting in cancer stem cell resistance to immunotherapy. Immunological-related lncRNAs can influence immune responses either directly by affecting neighboring protein-coding genes or indirectly by sponging miRNAs through various mechanisms. We have emphasized the role and levels of expression of lncRNAs that have been linked to immune cell formation, differentiation, and activation, which may have an influence on immunotherapy efficacy.

Background: Myoglobin (MB) is increasingly recognized as a key player in cancer growth and metastasis. Low oxygen tensions, commonly associated with highly aggressive and recurrent cancers, have been shown to regulate its expression in several cancers such as lung, neck, prostate and breast cancer. However, it is not yet known whether it contributes to the growth and spread of brain cancers especially Glioblastoma multiforme (GBM).Methods: Here we investigate the expression of MB, and its correlation with the hypoxia markers carbonic anhydrase IX (CAIX) and lactate dehydrogenase A (LDHA), in human tissue microarrays of multiple organ tumors, brain tumors, and GBM tumors, and their respective cancer-adjacent normal tissues. Correlation between MB protein expression and tumor grade was also assessed.Results: We show that MB protein is expressed in a wide variety of cancers, benign tumors, cancer-adjacent normal tissues, hyperplastic tissue samples and normal brain tissue, and low oxygen tensions modulate MB protein expression in different brain cancers, including GBM. Enhanced nuclear LDHA immune-reactivity in GBM was also observed. Finally, we report for the first time a positive correlation between MB expression and brain tumor grade.Conclusion: Our data suggest that hypoxia regulate MB expression in different brain cancers (including GBM) and that its expression is associated with a more aggressive phenotype as indicated by the positive correlation with the brain tumor grade. Additionally, a role for nuclear LDHA in promoting aggressive tumor phenotype is also suggested based on enhanced nuclear expression which was observed only in GBM.