Ntlotlang Mokgautsi

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, with resistance to targeted therapies presenting a significant clinical challenge. This study combines computational and experimental methods to identify and validate Antrocin, a natural sesquiterpene lactone, as a potential multi-target inhibitor of the BRAF/MEK/PI3K oncogenic pathway in CRC. Differential gene expression and mutational analyses were performed using public datasets (TCGA, TNMplot, GEPIA2, GSCA, PANDA, and cBioPortal) to assess the prevalence and clinical significance of BRAF, MEK, and PI3K alterations in CRC. In silico molecular docking, using AutoDock Vina, predicted strong binding affinities of Antrocin to BRAF (ΔG = −8.5 kcal/mol), MEK (ΔG = −7.3 kcal/mol), and PI3K (ΔG = −6.9 kcal/mol), comparable to those of FDA-approved inhibitors for BRAF (Dabrafenib), MEK (Trametinib), and PI3K (Alpelisib). Drug-likeness and ADME properties were evaluated via SwissADME and ADMETlab, supporting Antrocin’s potential as a drug candidate. In vitro assays using HCT116 and RKO CRC cell lines validated that Antrocin treatment suppressed cell viability, spheroid formation, and migration, accompanied by reduced expression levels of the oncogenic BRAF/MEK/PI3K signaling pathway. Antrocin-treated tumor-conditioned medium experiments demonstrated Antrocin’s ability to reduce the differentiation of cancer-associated fibroblasts and the polarization of M2 macrophages. Preclinical mouse xenograft experiments demonstrated a delay in tumor growth following treatment with Antrocin. These results suggest that Antrocin, identified through computational screening and validated experimentally, could be a promising multi-target agent to overcome therapy resistance in CRC.

In the original publication, there is a mistake in Figure 11B as published

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, β-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells’ presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle’s main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan–Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.

Tumor angiogenesis and lymphangiogenesis pathways have been identified as important therapeutic targets in non-small cell lung cancer (NSCLC). Bevacizumab, which is a monoclonal antibody, was the initial inhibitor of angiogenesis and lymphangiogenesis that received approval for use in the treatment of advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. Despite its usage, patients may still develop resistance to the treatment, which can be attributed to various histological subtypes and the initiation of treatment at advanced stages of cancer. Due to their better specificity, selectivity, and safety compared to chemotherapy, small molecules have been approved for treating advanced NSCLC. Based on the development of multiple small-molecule antiangiogenic drugs either in house and abroad or in other laboratories to treat NSCLC, we used a quinoline-derived small molecule—HN-N07—as a potential target drug for NSCLC. Accordingly, we used computational simulation tools and evaluated the drug-likeness properties of HN-N07. Moreover, we identified target genes, resulting in the discovery of the target BIRC5/HIF1A/FLT4 pro-angiogenic genes. Furthermore, we used in silico molecular docking analysis to determine whether HN-N07 could potentially inhibit BIRC5/HIF1A/FLT4. Interestingly, the results of docking HN-N07 with the BIRC5, FLT4, and HIF1A oncogenes revealed unique binding affinities, which were significantly higher than those of standard inhibitors. In summary, these results indicate that HN-N07 shows promise as a potential inhibitor of oncogenic signaling pathways in NSCLC. Ongoing studies that involve in vitro experiments and in vivo investigations using tumor-bearing mice are in progress, aiming to evaluate the therapeutic effectiveness of the HN-N07 small molecule.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3β/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute’s human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3β/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein–ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Colorectal cancer (CRC) is one of the most common cancers, and it frequently metastasizes to the liver and lymph nodes. Despite major advances in treatment modalities, CRC remains a poorly characterized biological malignancy, with high reported cases of deaths globally. Moreover, cancer stem cells (CSCs) and their microenvironment have been widely shown to promote colon cancer development, progression, and metastasis. Therefore, an understanding of the underlying mechanisms that contribute to the maintenance of CSCs and their markers in CRC is crucial in efforts to treat cancer metastasis and develop specific therapeutic targets for augmenting current standard treatments. Herein, we applied computational simulations using bioinformatics to identify potential theranostic markers for CRC. We identified the overexpression of vascular endothelial growth factor-α (VEGFA)/β-catenin/matrix metalloproteinase (MMP)-7/Cluster of Differentiation 44 (CD44) in CRC to be associated with cancer progression, stemness, resistance to therapy, metastasis, and poor clinical outcomes. To further investigate, we explored in silico molecular docking, which revealed potential inhibitory activities of LCC-21 as a potential multitarget small molecule for VEGF-A/CTNNB1/MMP7/CD44 oncogenic signatures, with the highest binding affinities displayed. We validated these finding in vitro and demonstrated that LCC-21 inhibited colony and sphere formation, migration, and invasion, and these results were further confirmed by a Western blot analysis in HCT116 and DLD-1 cells. Thus, the inhibitory effects of LCC-21 on these angiogenic and onco-immunogenic signatures could be of translational relevance as potential CRC biomarkers for early diagnosis.

Our previous study found that 2-phenyl-4-quinolone (2-PQ) derivatives are antimitotic agents, and we adopted the drug design concept of scaffold hopping to replace the 2-aromatic ring of 2-PQs with a 4-aromatic ring, representing 4-phenyl-2-quinolones (4-PQs). The 4-PQ compounds, whose structural backbones also mimic analogs of podophyllotoxin (PPT), maybe a new class of anticancer drugs with simplified PPT structures. In addition, 4-PQs are a new generation of anticancer lead compounds as apoptosis stimulators. On the other hand, previous studies showed that 4-arylcoumarin derivatives with 5-, 6-, and 7-methoxy substitutions displayed remarkable anticancer activities. Therefore, we further synthesized a series of 5-, 6-, and 7-methoxy-substituted 4-PQ derivatives (19–32) by Knorr quinoline cyclization, and examined their anticancer effectiveness. Among these 4-PQs, compound 22 demonstrated excellent antiproliferative activities against the COLO205 cell line (50% inhibitory concentration (IC₅₀) = 0.32 μM) and H460 cell line (IC₅₀ = 0.89 μM). Furthermore, we utilized molecular docking studies to explain the possible anticancer mechanisms of these 4-PQs by the docking mode in the colchicine-binding pocket of the tubulin receptor. Consequently, we selected the candidate compounds 19, 20, 21, 22, 25, 27, and 28 to predict their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. Pharmacokinetics (PKs) indicated that these 4-PQs displayed good drug-likeness and bioavailability, and had no cardiotoxic side effects or carcinogenicity, but we detected risks of drug–drug interactions and AMES toxicity (mutagenic). However, structural modifications of these 4-PQs could improve their PK properties and reduce their side effects, and their promising anticancer activities attracted our attention for further studies.

Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene’s overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G₁/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G₂/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G₁ phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis.