RAD54 and BLM helicase play pivotal roles during homologous recombination repair (HRR) to ensure genome maintenance. BLM amino acids (aa 181–212) interact with RAD54 and enhance its chromatin remodeling activity. Functionally, this interaction heightens HRR, leading to a decrease in residual DNA damage in colon cancer cells. This contributes to chemoresistance in colon cancer cells against cisplatin, camptothecin, and oxaliplatin, eventually promoting tumorigenesis in preclinical colon cancer mouse models. ChIP-Seq analysis and validation revealed increased BLM and RAD54 corecruitment on the MRP2 promoter in camptothecin-resistant colon cancer cells, leading to BLM-dependent enhancement of RAD54-mediated chromatin remodeling. We screened the Prestwick small-molecule library, with the intent to revert camptothecin- and oxaliplatin-induced chemoresistance by disrupting the RAD54-BLM interaction. Three FDA/European Medicines Agency–approved candidates were identified that could disrupt this interaction. These drugs bound to RAD54, altered its conformation, and abrogated RAD54-BLM–dependent chromatin remodeling on G5E4 and MRP2 arrays. Notably, the small molecules also reduced HRR efficiency in resistant lines, diminished anchorage-independent growth, and hampered the proliferation of tumors generated using camptothecin- and oxaliplatin-resistant colon cancer cells in both xenograft and syngeneic mouse models in BLM-dependent manner. Therefore, the 3 identified small molecules can serve as possible viable candidates for adjunct therapy in colon cancer treatment.

Over the recent years, immunomodulators have opened a new avenue in cancer treatment by virtue of their ability to boost the immune system for neoplastic cell elimination. Improving treatment outcomes by leveraging the interaction of these agents with traditional cancer treatments is the main emphasis of this review. Checkpoint inhibitors, chemokine receptors, and pattern recognition receptors are the immunological targets of their interactive mechanisms. Immunomodulators are generally categorized as inhibitors of checkpoint, cytokines, agonists, or adjuvants. Despite their high efficacy and specificity, modern-day antibody-based therapies face several key limitations such as immunogenicity, insufficient tissue penetration, and restricted oral bioavailability. To address these shortcomings, researchers are crafting small molecules with the potential for oral administration and improved pharmacokinetic properties. These agents can augment antibody therapies for synergistic effects to enhance therapeutic efficacy for different types of cancers. This review explores the synergy between immunomodulators and traditional cancer treatments (chemotherapy, radiation, and targeted therapies) as well as newer strategies like adoptive cell therapies (chimeric antigen receptor therapies such as chimeric antigen receptor-T (CAR-T) cell therapy and chimeric antigen receptor-natural killer (CAR-NK)). These combinations improve treatment effectiveness in a number of ways: radiotherapy increases tumor antigen presentation and T-cell infiltration, chemotherapy-induced immunogenic cell death boosts immune responses and targeted therapies lessen immunosuppression in the tumor microenvironment. Despite the potential appeal as adjuvants, immunomodulators also pose challenges in maximizing their efficacy and minimizing adverse effects. In this paper, clinical trials proving the effectiveness of these combined techniques are reviewed, and innovative approaches including next-generation checkpoint inhibitors and delivery systems based on nanoparticles are also highlighted. Overall, this review evaluates the existing impact of immunomodulatory adjuvants and their prospective trends in cancer care. Further development of immunomodulators will pave the way for more accessible and effective therapies, marking a significant step towards personalized oncological interventions.

Introduction: Diabetes mellitus (DM) is a multimodal metabolic disease whose world inci-dence is estimated to reach approximately 366 million by the year 2030, even with the progress being made in biomedical research. The interaction of genetics, lifestyle, and environment complicates its management. Dipeptidyl peptidase IV (DPP-IV) and α-glucosidase inhibition a promising therapies: DPP-IV inhibition increases the effect of incretin and the release of insulin, and α-glucosidase inhibition postpones carbohydrate digestion and glucose absorption. Methods: Molecular docking and density functional theory (DFT) were employed to explore the anti-diabetic effect of stigmasterol, a phytosterol with Glycine max. Docking experiments were conducted to determine the binding affinities and interaction patterns between stigmasterol and DPP-IV and α-glucosidase. DFT analysis was done to obtain global reactivity descriptors and energy band gap, which estimated the electronic stability and reactivity of the molecule. Results: Stigmasterol exhibited high affinity towards the two target enzymes with docking scores of -8.8 kcal/mol to DPP-IV and -8.4 kcal/mol to α-galactosidase. The analysis of the DFT showed that it had a good (moderate) band gap and unaltered electronic configuration, which is indicative of good chemical reactivity and stability. Discussion: The binding affinities and electronic properties indicate that stigmasterol can be a dual DPP-IV and α-glucosidase inhibitor, which can be used synergistically to produce synergistic glycemic control via the regulation of incretin-mediated insulin release and postprandial carbohydrate absorption. The computational findings are in favor of its candidacy as a natural antidiabetic compound, but the weaknesses of in silico studies demand experimental confirmation. Conclusion: Stigmasterol has been suggested as a promising dual DPP-IV and alpha-glucosidase inhib-itor that could be useful in the management of diabetes mellitus. It needs to be further tested in vitro and in vivo to verify its biological efficacy, pharmacokinetics, and safety profile.