Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC.

Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.

Several sesquiterpene lactones (STLs) have been tested as lead drugs in cancer clinical trials. Salograviolide-A (Sal-A) and salograviolide-B (Sal-B) are two STLs that have been isolated from Centaurea ainetensis, an indigenous medicinal plant of the Middle Eastern region. The parent compounds Sal-A and Sal-B were modified and successfully prepared into eight novel guaianolide-type STLs (compounds 1–8) bearing ester groups of different geometries. Sal-A, Sal-B, and compounds 1–8 were tested against a human colorectal cancer cell line model with differing p53 status; HCT116 with wild-type p53 and HCT116 p53^−/− null for p53, and the normal-like human colon mucosa cells with wild-type p53, NCM460. IC₅₀ values indicated that derivatization of Sal-A and Sal-B resulted in potentiation of HCT116 cell growth inhibition by 97% and 66%, respectively. The effects of the different molecules on cancer cell growth were independent of p53 status. Interestingly, the derivatization of Sal-A and Sal-B molecules enhanced their anti-growth properties versus 5-Fluorouracil (5-FU), which is the drug of choice in colorectal cancer. Structure-activity analysis revealed that the enhanced molecule potencies were mainly attributed to the position and number of the hydroxy groups, the lipophilicity, and the superiority of ester groups over hydroxy substituents in terms of their branching and chain lengths. The favorable cytotoxicity and selectivity of the potent molecules, to cancer cells versus their normal counterparts, pointed them out as promising leads for anti-cancer drug design.

Background: Colorectal cancer (CRC) is the third most common cancer globally. Atorvastatin (ATR), a lipid-lowering drug, has shown promise as a repurposed therapeutic agent for CRC. However, its clinical application is limited by poor solubility and low oral bioavailability. This study aimed to optimize ATR-loaded chitosan-coated cubosomes using a Box–Behnken design and evaluate their potential in CRC treatment through physicochemical characterization and cell viability studies on HCT116 human CRC cells. Methods: Optimized cubosomes were characterized for particle size, zeta potential, polydispersity index (PDI), drug content, entrapment efficiency, compatibility using Fourier transform infrared spectroscopy, and in vitro release in various pH media. Cytotoxic effects were assessed using sulforhodamine B and trypan blue viability assays. Results: Uncoated cubosomes exhibited a particle size of 120.0 ± 1.66 nm, a zeta potential of −22.2 ± 1.05 mV, and a PDI of 0.136 ± 0.01. The chitosan-coated cubosomes displayed a size of 169.3 ± 4.14 nm, a zeta potential of 29.7 ± 0.814 mV, and a PDI of 0.245 ± 0.015. Entrapment efficiency and drug content were 92.1 ± 2.46% and 64.5 ± 1.58%, respectively. The ATR-loaded cubosomes demonstrated pH-dependent release, negligible at pH 1.2 and 4.5, but pronounced at pH 6.8 and 7.4, supporting colon-targeted delivery. Cell viability studies showed significant inhibition of HCT116 cells at ATR concentrations of 1 and 5 µM, with complete inhibition at higher doses. Conclusions: Chitosan-coated ATR-loaded cubosomes are promising for targeting ATR delivery to the colon. They offer enhanced anticancer activity by bypassing gastric degradation and systemic circulation, making an efficient approach to CRC treatment.

Cancer is a major public health problem that ranks as the second leading cause of death. Anti-cancer drug development presents with various hurdles faced throughout the process. Nanoparticle (NP) formulations have emerged as a promising strategy for enhancing drug delivery efficiency, improving stability, and reducing drug toxicity. Previous studies have shown that the adamantyl retinoid ST1926 displays potent anti-tumor activities in several types of tumors, particularly in colorectal cancer (CRC). However, phase I clinical trials in cancer patients using ST1926 are halted due to its low bioavailability. In this manuscript, we developed ST1926-NPs using flash nanoprecipitation with polystyrene-b-poly (ethyleneoxide) as an amphiphilic stabilizer and cholesterol as a co-stabilizer. Dynamic light scattering revealed that the resulting ST1926-NPs Contin diameter was 97 nm, with a polydispersity index of 0.206. Using cell viability, cell cycle analysis, and cell death assays, we showed that ST1926-NP exhibited potent anti-tumor activities in human CRC HCT116 cells. In a CRC xenograft model, mice treated with ST1926-NP exhibited significantly lowered tumor volumes compared to controls at low drug concentrations and enhanced the delivery of ST1926 to the tumors. These findings highlight the potential of ST1926-NPs in attenuating CRC tumor growth, facilitating its further development in clinical settings.