Rhein exerts anti-multidrug resistance in acute myeloid leukemia via targeting FTO to inhibit AKT/mTOR.

Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.

Multifaceted effects of LRP6 in cancer: exploring tumor development, immune modulation and targeted therapies.

Low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6), a member of the LDLR superfamily of cell surface receptors, is most widely known as a crucial co-receptor in the activation of canonical Wnt/ß-catenin signaling. This signaling pathway is implicated in multiple biological processes, such as lipoprotein metabolism, protease regulation, cell differentiation, and migration. LRP6 is frequently overexpressed in a variety of tumors, including liver cancer, colorectal cancer, and prostate cancer, and is generally considered an oncogene that promotes tumor proliferation, migration, and invasion. However, there are exceptions; some studies have reported that LRP6 inhibits lung metastasis of breast cancer through its ectodomain (LRP6N), and patients with low LRP6 expression tend to have a poor prognosis. Thus, the role of LRP6 in tumors remains controversial. Although limited studies have shown that LRP6 is associated with the expression and roles of a variety of immune cells in tumors, the interaction of LRP6 with the tumor microenvironment (TME) is not fully understood. Furthermore, it is crucial to acknowledge that LRP6 can engage with alternative pathways, including the mTORC1, CXCL12/CXCR4, and KRAS signaling pathways mentioned earlier, resulting in the regulation of biological functions independent of canonical Wnt/ß-catenin signaling. Due to the potential of LRP6 as a molecular target for cancer therapy, various treatment modalities have been developed to directly or indirectly inhibit LRP6 function, demonstrating promising anti-cancer effects across multiple cancer types. This review will concentrate on exploring the expression, function, and potential therapeutic applications of LRP6 in different cancer types, along with its influence on the TME.

MP-13, a novel chimeric peptide of morphiceptin and pepcan-9, produces potent antinociception with limited side effects.

Pharmacological investigations have substantiated the potential of bifunctional opioid/cannabinoid agonists in delivering potent analgesia while minimizing adverse reactions. Peptide modulators of cannabinoid receptors, known as pepcans, have been investigated before. In this study, we designed a series of chimeric peptides based on pepcans and morphiceptin (YPFP-NH2). Here, we combined injections of pepcans and morphiceptin to investigate the combination treatment of opioids and cannabis and compared the analgesic effect with chimeric compounds. Subsequently, we employed computational docking to screen the compounds against opioid and cannabinoid receptors, along with an acute pain model, to identify the most promising peptide. Among these peptides, MP-13, a morphiceptin and pepcan-9 (PVNFKLLSH) construct, exhibited superior supraspinal analgesic efficacy in the tail-flick test, with an ED50 value at 1.43 nmol/mouse, outperforming its parent peptides and other chimeric analogs. Additionally, MP-13 displayed potent analgesic activity mediated by mu-opioid receptor (MOR), delta-opioid receptor (DOR), and cannabinoid type 1 (CB1) receptor pathways. Furthermore, MP-13 did not induce psychological dependence and gastrointestinal motility inhibition at the effective analgesic doses, and it maintained non-tolerance-forming antinociception throughout a 7-day treatment regimen, with an unaltered count of microglial cells in the periaqueductal gray region, supporting this observation. Moreover, intracerebroventricular administration of MP-13 demonstrated dose-dependent antinociception in murine models of neuropathic, inflammatory, and visceral pain. Our findings provide promising insights for the development of opioid/cannabinoid peptide agonists, addressing a crucial gap in the field and holding significant potential for future research and development. PERSPECTIVE: This article offers insights into the combination treatment of pepcans with morphiceptin. Among the chimeric peptides, MP-13 exhibited potent analgesic effects in a series of preclinical pain models with a favorable side-effect profile.