Glioblastoma is one of the most aggressive brain cancers, characterized by active infiltrative growth and high resistance to radiotherapy and chemotherapy. Sesquiterpene triterpenoids (STLs) and their semi-synthetic analogs are considered as a promising source of novel anti-tumor agents due to their low systemic toxicity and multi-target pharmacological effects on key processes associated with tumor progression. The current review aims to systematize the knowledge on the anti-glioblastoma potential of STLs accumulated over the last decade and to identify key processes in glioblastoma cells that are most susceptible to the action of STLs. An analysis of published data clearly demonstrated that STLs, which can successfully cross the blood–brain barrier, exert a complex inhibitory effect on glioblastoma cells through the induction of the “mitochondrial dysfunction–oxidative stress–apoptosis” axis, the inhibition of glucose metabolism and cell cycle phase transition, and the suppression of glioblastoma cell motility and invasion through the blockade of proneural–mesenchymal transition. Taken together, this review highlights the promising anti-glioblastoma potential of STLs, which are not only able to induce glioblastoma cell death, but also effectively affect their diffusive spread, and suggests the possible directions for further investigation of STLs in the context of glioblastoma to better understand their mechanism of action.

Multidrug resistance (MDR) remains a significant challenge in cancer therapy, primarily due to the overexpression of transmembrane drug transporters, with P-glycoprotein (P-gp) being a central focus. Consequently, the development of P-gp inhibitors has emerged as a promising strategy to combat MDR. Given the P-gp targeting potential of soloxolone amides previously predicted by us by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, the aim of the current study was to experimentally verify their P-gp inhibitory and MDR reversing activities in vitro. Screening of soloxolone amides as modulators of P-gp using molecular docking and cellular P-gp substrate efflux assays revealed the ability of compound 4 bearing a N-3-(dimethylamino)propylamide group to interact with the active site of P-gp and inhibit its transport function. Blind and site-specific molecular docking accompanied by a kinetic assay showed that 4 directly binds to the P-gp transmembrane domain with a binding energy similar to that of zosuquidar, a third-generation P-gp inhibitor (ΔG = −10.3 kcal/mol). In vitro assays confirmed that compound 4 enhanced the uptake of Rhodamine 123 (Rho123) and doxorubicin (DOX) by the P-gp-overexpressing human cervical carcinoma KB-8-5 (by 10.2- and 1.5-fold, respectively (p < 0.05, unpaired t-test)) and murine lymphosarcoma RLS40 (by 15.6- and 1.75-fold, respectively (p < 0.05, unpaired t-test)) cells at non-toxic concentrations. In these cell models, 4 showed comparable or slightly higher activity than the reference inhibitor verapamil (VPM), with the most pronounced effect of the hit compound in Rho123-loaded RLS40 cells, where 4 was 2-fold more effective than VPM. Moreover, 4 synergistically restored the sensitivity of KB-8-5 cells to the cytotoxic effect of DOX, demonstrating MDR reversal activity. Based on the data obtained, 4 can be considered as a drug candidate to combat the P-gp-mediated MDR of tumor cells and semisynthetic triterpenoids, with amide moieties in general representing a promising scaffold for the development of novel therapeutics for tumors with low susceptibility to antineoplastic agents.

Background: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its efficacy is often limited by cancer cell resistance. Although multiple DOX resistance mechanisms have been characterized, the global transcriptomic alterations underlying this phenomenon remain poorly understood. The aim of this work was to determine whether a common transcriptional response associated with DOX desensitization exists across tumor cells of different origins and to identify the core elements of this response. Methods: We performed an integrated bioinformatics analysis, including: analysis of independent transcriptomic datasets (comparing DOX-resistant neuroblastoma, breast, and cervical carcinoma cells to their DOX-sensitive counterparts), functional annotation of differentially expressed genes, reconstruction and topology analysis of gene networks, text mining, and survival analysis. The findings were validated through in vitro functional tests, RT-PCR, and analysis of the Cancer Therapeutics Response Portal and The Cancer Genome Atlas. Results: We showed that DOX resistance in cancer cells is associated with cytoskeletal reorganization, modulation of cell adhesion, cholesterol biosynthesis, and dysregulation of mTORC1, Wnt, and Gβγ signaling pathways. Network analysis identified a conserved regulome of 37 resistance-linked genes, with GJA1, SEH1L, TCF3, TUBA4A, and ZYX emerging as central hubs (mean degree: 8.7–19.7; mean fold change: 2.4–21.3). Experimental validation in DOX-resistant KB-8-5 cervical carcinoma cells and their sensitive counterparts (KB-3-1) confirmed enhanced cellular adhesion and reduced intracellular cholesterol levels associated with chemoresistance, supporting our in silico findings. A detailed follow-up analysis verified the upregulation of these hub genes in chemoresistant cells and their correlation with poor clinical outcomes across multiple cancer types. Conclusions: This integrative analysis identifies conserved transcriptomic signatures of DOX resistance and highlights hub genes GJA1, SEH1L, TCF3, TUBA4A, and ZYX with potential as predictive biomarkers and therapeutic targets. Targeting these pathways may help overcome chemoresistance and improve treatment outcomes in cancer patients.

Background: Chemotherapy remains one of the main approaches for treating malignant tumors, but repeated exposure to cytostatics leads to multidrug resistance (MDR), increasing tumor aggressiveness and reducing therapeutic efficacy. Identifying adjuvant agents that restore tumor sensitivity to drugs while minimizing toxicity is a cornerstone challenge today. This study aimed to investigate the potential of mesyl phosphoramidate antisense oligonucleotides (µ-ASOs) targeting miR-17, miR-21, and miR-155 as agents for enhancing the efficacy of cisplatin (Cis) and doxorubicin (Dox) in MDR-positive human epidermoid carcinoma KB-8-5 cells. Methods: Optimal regimens for the simultaneous application of µ-ASOs and Dox or Cis in KB-8-5 cells, including a concentration-dependent analysis and the type of compound interaction in combinations (synergy/additivity/antagonism), were studied using the MTT assay. Antiproliferative effects of the combinations were assessed using the real-time cell monitoring xCELLigence system. The potential molecular mechanism underlying KB-8-5 cell sensitization to cytostatics was investigated using RT-PCR and Western blot hybridization, supported by bioinformatic reconstruction of the gene network. Results: The most effective combinations including µ-ASOs targeting miR-21 and miR-17 together with Cis or Dox demonstrated additive to moderately synergistic effects on KB-8-5 cell viability (HSA synergy score = 4.8–8.7). The co-application of µ-ASOs allowed a 5- to 20-fold reduction in the dose of cytostatics, while maintaining a strong antiproliferative effect of 70–95%. Sensitization of KB-8-5 cells to Cis or Dox following µ-ASO treatment was mediated by a 1.5- to 3-fold decrease in the levels of the well-known MDR marker ABCB1 as well as the newly identified MDR-associated targets ZYX, TUBA4A, and SEH1L. Conclusions: miRNA-targeted mesyl phosphoramidate oligonucleotides are effective tools for overcoming resistance to the clinically approved chemotherapeutics cisplatin and doxorubicin. The relationship between miR-21, miR-17, and miR-155 and the novel MDR markers such as SEH1L, TUBA4A, and ZYX was revealed, thereby expanding the current understanding of the molecular mechanisms underlying tumor cell resistance to chemotherapy.

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants.