Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included “lidocaine”, “ropivacaine”, “levobupivacaine”, “morphine”, “methadone”, “breast cancer”, “breast carcinoma” and “breast neoplasms” in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients’ treatment.

The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients.

Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers.

Background and Purpose Plectranthus spp. have been traditionally used to treat various ailments, including cancer. Among their bioactive components, 7α-acetoxy-6β-hydroxyroyleanone 1 and 6,7-dehydroroyleanone 2 showed notable antiproliferative activity against several cancer cell lines. The present study investigates abietane diterpenoids 1 and 2 as lead compounds for breast cancer therapeutics targeting protein kinase C-α (PKC-α), a family of enzymes linked to carcinogenesis and challenging to modulate selectively. Experimental Approach Molecular docking was employed to explore hydroxyl group modifications on compounds 1 and 2 to enhance PKC-α C1 domain binding. Selected derivatives were evaluated for antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cell lines., and for cytotoxicity on non-tumorigenic fibroblasts (HFF-1). PKC-α activation was assessed using yeast-based and kinase activity assays. Key Results Docking studies supported the synthesis of seven derivatives, leading to 18 compounds from abietane diterpenoid 1 (yields: 7% to 93%). Compound 1 showed strong antiproliferative activity but high HFF-1 cytotoxicity. Derivatives 3d-h and 5k demonstrated the most promising results, with lower IC ₅₀ value and enhanced electivity and were selected for PKC-α modulation studies. In yeast-based assays, compounds 1 , 3d , and 5k activated PKC-α, with 3d showing the strongest effect. This was corroborated by the PKC kinase activity assay, where 3d outperformed the positive control (PMA) in activating PKC-α. These findings are consistent with the docking predictions, as 3d ranked among the top candidates. Conclusion and Implications Derivative 3d emerged as a potent and selective PKC-α activator, making it a promising lead for further development in breast cancer therapeutics.