Danijela Maksimović-Ivanić

Multiple studies have demonstrated that the conjugation of various metal cores to a modified tamoxifen vector amplifies its antitumor activity, rendering such engineered structures effective even in triple-negative breast cancer (TNBC), a tumor subtype traditionally considered irrelevant for endocrine therapy. With a focus on TNBC cell line, this study shows that hybrids with Pd- and Cu- in comparison to Pt-based counterparts exerted an advanced cytotoxic profile in terms of sustained cytotoxicity throughout all tested periods, well synchronized with an intensive and prolonged oxidative burst measured by 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM), dihydroethidium (DHE), and dihydrorhodamine 123 (DHR-123) in the background. Translation to the orthotopic syngeneic mouse in vivo model confirmed their superiority toward Pt-based conjugates, as well as tamoxifen alone, with a more profound tumor-reducing potential of Cu-tamoxifen, which was finally restricted by its toxicity. Surprisingly, the tamoxifen vector per se, with an approx. 2-fold lower cytotoxic potential than Pt- and Cu-hybrids in vitro, showed exceptional tumor-reducing potential in vivo, profiled in the last days of the treatment period. Intensive infiltration of immune cells, preferentially lymphocytes, was observed in tumor samples from animals exposed to the tamoxifen vector, underscoring the ligand’s immune potential and again suggesting that cytotoxicity is not a measure of successful treatment.

Driven by the high incidence of colorectal cancer (CRC) globally, current research is focused on a multitarget strategy to inhibit inflammatory pathways and malignant cell proliferation simultaneously. In this context, elevated expression of the COX-2 enzyme plays a critical role in tumor progression. Chalcones (1,3-diaryl-2-propen-1-ones) stand out as highly promising scaffolds due to their diverse biological activities; by inhibiting COX-2, these compounds operate through a dual-action mechanism that effectively suppresses inflammatory pathways while exerting a direct cytotoxic effect on cancer cells. This study aimed to evaluate the in vitro anticancer effect of 16 structurally diverse aminoand morpholino-chalcones with various substituents on the second aromatic ring. Cytotoxicity was assessed using four CRC cell lines (HCT116, HT29, SW480, and MC38) and one healthy cell line (MRC-5). Following 72-hour incubation, cell viability was measured using MTT and crystal violet (CV) assays to determine IC50 values. All derivatives demonstrated dose-dependent cytotoxicity, and the SW480 line exhibited the highest sensitivity. Significantly higher IC50 values in non-malignant MRC-5 cells confirmed favourable tumor selectivity for all compounds. The most potent derivatives were chalcones possessing groups with a negative inductive effect in the meta position of the second ring: aminochalcone labelled as 23 (m-F) and morpholinochalcone 51 (m-CN). Due to their pronounced differential cytotoxicity and lowest IC50, these derivatives represent the most promising leads for subsequent studies of their mechanism of action and the development of novel chemotherapeutic agents for colorectal cancer.

The significant side effects associated with platinum-based anticancer agents have driven the continuous pursuit of novel, non-platinum-based metal compounds. Ruthenium-based organometallic compounds have emerged as promising alternatives, owing to their distinctive and adaptable biochemical properties. The research efforts are focused on the development of ruthenacarborane-based anticancer drugs. The combination of ruthenium(II) complexes, recognized for their inherent anticancer potential, with carboranes, boron-rich clusters possessing unique chemical and physical characteristics, and NSAIDs, known to inhibit COX, an enzyme overexpressed in tumors, offers a novel approach for cancer therapy. Consequently, combining these three moieties into a single molecule represents a compelling strategy to develop drugs with a dual mode of action. Herein, we report the synthesis of a series of ruthenacarborane-(η⁶-p-cymene)–NSAID conjugates (4a, 4b, 5b, and 6b) by linking NSAIDs (flurbiprofen, fenoprofen, and ibuprofen) to ruthenacarborane complexes using methylene and ethylene spacers, while maintaining the integrity of the sensitive ester groups present in the system. The synthesized conjugates were thoroughly characterized using multinuclear (¹H, ¹¹B, and ¹³C) NMR spectroscopy. Notably, the conjugates demonstrated low COX inhibition and no cytotoxic potential against different cancer cell lines, probably due to oxidative deactivation confirmed by cyclic voltammetry (CV). This indicates that the conjugation of this type of ruthenacarborane with NSAIDs does not result in novel anticancer drugs.

Background/Objectives: Galectin-3 (Gal-3), encoded by LGALS3, is a β-galactoside-binding lectin involved in diverse tumor-associated processes, including immune modulation, cell cycle regulation, and stress adaptation. Despite its known roles in cancer biology, the full extent of its molecular functions and prognostic relevance across tumor types remains incompletely understood. This study aimed to systematically investigate the transcriptomic impact of LGALS3 deletion and assess its clinical significance in cancer. Methods: We analyzed CRISPR-Cas9 knockout transcriptomic data from the SigCom LINCS database to characterize the consensus gene signature associated with LGALS3 loss using functional enrichment analyses. Pan-cancer survival analyses were conducted using TIMER2.0. Differential Gal-3 protein levels in ductal adenocarcinoma and normal pancreatic tissues were evaluated using the Human Protein Atlas. Finally, functional analyses were performed in pancreatic ductal adenocarcinoma (PDAC). Results: LGALS3 deletion across multiple cancer cell lines led to transcriptomic changes involving mitotic progression, stress responses, and axonal guidance pathways. High LGALS3 expression was significantly associated with worse overall survival in lower-grade glioma, PDAC, uveal melanoma, and kidney renal papillary cell carcinoma. LGALS3 knockout in YAPC cells recapitulated the pan-cancer findings, linking LGALS3 to cell morphogenesis and proliferation. Conclusions: These findings identify Galectin-3 as a key regulator of oncogenic programs and a potential prognostic biomarker in PDAC and other malignancies, with implications for therapeutic targeting.

The concept of hybrid drugs that integrate cytotoxic and anti-inflammatory activity, enabling the simultaneous delivery of a chemotherapeutic agent and a non-steroidal anti-inflammatory drug (NSAID) into the tumor microenvironment (TME), was created with the aim of blocking the mitogenic signals that lead to tumor renewal. Here, we provide for the first time a detailed insight into the mechanism of action of a platinum(IV) complex based on the cisplatin (CP) scaffold bearing two deprotonated NSAID ligands (naproxenate (Npx)) in axial position ([CP(Npx)₂]), free and immobilized in nanostructured silica SBA-15 (SBA-15|[CP(Npx)₂]), in a melanoma model. The conjugate in free or loaded form diminished the viability of cancer cells more potently than CP, with an exceptional preference for the malignant phenotype. Type I and II programed cell death, senescence, and terminal differentiation of the surviving cell fraction were the basic mechanisms of action by which the new hybrid molecule achieved its effect in vitro. In the mouse melanoma model, the application of the therapeutic agents led to a reduction in tumor volume, extinguishing of intratumoral inflammation, and an overall better toxicity profile compared to CP. Overall, this approach improved the efficacy of chemotherapy by removing obstacles that cause chronic inflammation in the TME.

The synthesis and characterization of novel platinum( ii ) and platinum( iv ) complexes derived from unsymmetrical ethylene or propylenediamine derivatives are presented.

Objectives: New tributyltin(IV) complexes containing the carboxylate ligands 3-(4-methyl-2-oxoquinolin-1(2H)-yl)propanoic acid (HL1) and 2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetic acid (HL2) have been synthesized. Methods: Their structures have been determined by elemental microanalysis, FT-IR and multinuclear NMR (¹H, ¹³C and ¹¹⁹Sn) spectroscopy and X-ray diffraction study. A solution state NMR analysis reveals a four-coordinated tributyltin(IV) complex in non-polar solvents, while an X-Ray crystallographic analysis confirms a five-coordinated trigonal-bipyramidal geometry around the tin atom due to the formation of 1D chains. A theoretical structural analysis was performed by optimization employing B3LYP-D3BJ functional and 6-311++G(d,p)/def2-TZVP(Sn) basis sets for H, C, N, O/Sn, respectively. The interactions between tin(IV) and surrounding atoms were examined by QTAIM approach. The in vitro antiproliferative activity of the synthesized compounds was evaluated by MTT and CV assays versus MCF-7 (human breast adenocarcinoma), HCT116 (human colorectal carcinoma), A375 (human melanoma), 4T1 (mouse breast carcinoma), CT26 (mouse colon carcinoma) and B16 (mouse melanoma) tumor cell lines. Results: Both synthesized compounds (nBu₃SnL1 and nBu₃SnL2) exerted powerful micromolar IC₅₀ cytotoxicity values and demonstrated high selectivity toward malignant cells. Both experimental drugs affected cell adhesion and induced anchorage independent apoptosis, a favorable type of cell death with an essential role in cancer dissemination prevention. The BSA-binding affinity of the obtained organotin compounds was followed by spectrofluorometric titration and molecular docking simulations. Conclusions: The tributyltin(IV) compounds selectively induce anoikis-like cell death in A375 cells, also highlighting the importance of the organic moiety on the tin(IV) ion in the mechanism of action.

Quinazolinones, particularly 9-azaglycophymines, and closely related derivatives and precursors were tested in vitro against various breast cancer cell lines representing the major types of breast tumors. Among the 49 compounds tested, azaglycophymine derivative 19 with an electron-withdrawing substituent demonstrated the most significant anti-proliferative effects, with IC₅₀ values of around 4 µM. Extensive cell-based investigations revealed that compound 19 induced caspase-dependent apoptosis in HCC1937 (human TNBC), BT-474 (human HER2+/HR+), and 4T1 (mouse TNBC) cells. In contrast, in MDA-MB-468 (human TNBC) and MCF-7 (human HR+) cells, the cell death was induced via a non-apoptotic pathway. The in vivo efficacy of compound 19 was validated using a syngeneic orthotopic 4T1 model in BALB/c mice, resulting in significant reduction of 4T1 breast tumor growth upon intraperitoneal (i.p.) application of doses of 5 or 20 mg/kg. These findings highlight the potential of compound 19 as a promising scaffold for the development of new therapeutic agents for various types of breast cancer and a first structure-activity insight.