Shanghai Fudan-Zhangjiang · TOP2A · Small Molecule
doxorubicin hydrochloride is a small molecule developed by Shanghai Fudan-Zhangjiang. It is approved for therapeutic indications via injectable (others) or intravenous (iv).
| Brand Names | Libod, Libaoduo |
| Company | Shanghai Fudan-Zhangjiang |
| Drug Class | Small Molecule |
| Molecular Target | TOP2A |
| Route | Injectable (Others), Intravenous (IV) |
| Status | Approved |
doxorubicin hydrochloride acts on 1 molecular target:
| TOP2A | DNA topoisomerase II alpha (TOP2alpha, TOPIIA) |
doxorubicin hydrochloride is developed for 4 unique indications across 1 therapeutic area.
| Therapeutic Area | Condition | Phase |
|---|---|---|
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Breast cancer | ✓ Approved |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Kaposi's sarcoma | ✓ Approved |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Ovarian cancer | ✓ Approved |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Plasma cell myeloma | ✓ Approved |
Wilky Breelyn A BA, Julian Katherine A KA, Maleddu Alessandra A, Mailhot Anne C AC et al.
Chen XiaoJie X, Lu YuYuan Y, Wang YiYuan Y, Kou YuShun Y et al.
Doxorubicin (DOX), a highly effective anthracycline chemotherapy drug, has its clinical application severely restricted by dose-dependent doxorubicin-induced cardiotoxicity (DIC). Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, has been confirmed as a core pathological mechanism in DIC, where it synergistically participates with multiple cell death modalities in myocardial injury. This review systematically elaborates the multidimensional molecular mechanisms underlying DOX-induced myocardial ferroptosis, including: lipid peroxidation cascade self-amplification, bidirectional regulation by selective autophagy, multilayered GPX4 modification and stability regulation, and involvement of the gut microbiota-heart axis. Concurrently, we summarize evidence for natural phytochemicals-including flavonoids, polyphenols, terpenoids, and traditional Chinese medicine compounds-that inhibit myocardial ferroptosis via multi-target mechanisms, providing theoretical support for phytochemical-based DIC intervention. Critically, this review addresses the clinical translation dilemmas in ferroptosis regulation and proposes three innovative strategies: (1) time-decoupling strategy based on IFN-γ signaling; (2) cardiac-targeted nanodrug delivery system employing the OGF/OGFR axis; (3) cross-regulation between ferroptosis and other regulated cell death pathways. These strategies aim to achieve tissue-selective ferroptosis intervention, simultaneously protecting myocardium while maintaining DOX anti-tumor efficacy, thereby providing molecular mechanistic basis and clinical translational directions for constructing precision ferroptosis-targeted cardioprotective strategies.
Kumar Vinod V, Kanika, Khan Rehan R, Ghosh Amrita A et al.
Hydrogen sulfide (H2S) is a key endogenous gaseous messenger, and its abnormal levels are closely linked to major physiological and pathological conditions. Developing selective and water-compatible H2S probes is therefore crucial. In this work, we report an amphiphilic naphthalimide-DPA-based fluorescent probe (Nap.Amp) capable of sequential Cu2+ and H2S detection via a fluorescence ON-OFF-ON mechanism. Nap.Amp exhibits strong green fluorescence that is quenched upon the formation of an in situ copper complex (Nap.Amp-Cu), which in turn displays excellent selectivity toward H2S, restoring the emission signal through copper displacement. To enhance aqueous solubility and sensing efficiency, Nap.Amp was incorporated into DOPC liposomes to generate nanoscale vesicles (Nap.Lipo). This liposomal system showed significantly improved Cu2+ affinity, forming nanoaggregates that served as a sensitive platform for H2S recognition. The Nap.Lipo-Cu ensemble detected H2S with a low LOD of 1.62 μM, and the sensing mechanism was validated using DLS and SEM analyses. Beyond solution-phase studies, Nap.Amp-Cu was adapted into portable test formats such as double-chamber gas sensors, paper strips, and alginate hydrogel beads for rapid, instrument-free H2S detection. Nap.Lipo also demonstrated excellent biocompatibility and enabled fluorescence imaging of H2S in L929 cells. Overall, this work presents the first demonstration of a liposome-incorporated naphthalimide-DPA probe (Nap.Amp) as a robust, versatile nanosensor for environmental and biological H2S detection.
Cui Chaochu C, Zhao Jinyu J, Li Xiaoqian X, Huang Shengming S et al.
Prolonged survival of patients with cancer has increased the need to address chemotherapy‑related cardiovascular complications. Doxorubicin (DOX), a widely used anthracycline, is associated with dose‑dependent cardiotoxicity, known as DOX‑induced cardiotoxicity (DIC), which limits its clinical utility. DOX triggers cardiomyocyte pyroptosis via the NLRP3/caspase‑1/gasdermin D pathway, a potential underlying mechanism of DIC. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of lipid metabolism and inflammation, has been implicated in NLRP3 inflammasome activation and the progression of cardiovascular diseases; however, its role in DIC remains unclear. The present study demonstrated that DOX downregulates PCSK9 expression in cardiomyocytes in a dose‑dependent manner. Through proteomic analysis and PCSK9 knockout cell and mouse models, it was found that the deletion of PCSK9 exacerbated DOX‑induced pyroptosis and cardiac dysfunction. These results revealed the protective effect of PCSK9 in DOX‑mediated cardiotoxicity and indicated that PCSK9 regulation may provide a new cardioprotective strategy for patients receiving anthracycline chemotherapy.
Inde Zintis Z, Keppler Sebastian S, Gelles Jesse J, Fraser Cameron S CS et al.
Small molecule inhibitors of cell death have wide-ranging potential applications, both as tool compounds in the laboratory and as clinical modulators of pathologic cell death. Previous screening efforts have identified candidate compounds targeting the pro-apoptotic, pore-forming BCL-2 family proteins BAX and BAK, but the complex interactions of these proteins at the mitochondrial outer membrane (with other proteins and the membrane itself) present challenges for compound screening. Although no inhibitors of BAX or BAK have advanced to clinical testing to date, candidate inhibitors have thus far been identified via screening of membrane-containing systems such as liposomes and isolated mitochondria. To address some of the challenges of chemical screening for apoptosis inhibitors, we conducted a small molecule screen utilizing BH3 profiling, a method that quantifies mitochondrial outer membrane permeabilization (MOMP) upon treatment with pro-apoptotic peptides derived from BCL-2 family proteins. Of over 40,000 compounds screened, we identified a series of compounds that prevent MOMP in response to pro-apoptotic peptides. The most potent of these, CDL36, binds to BAX and prevents MOMP at early timepoints. In longer term viability assays, the cytoprotective effect of CDL36 is most potent against death induced by doxorubicin, a widely used chemotherapeutic agent that causes dose-limiting cardiovascular toxicity. Our results elucidate the mechanism of action of new and existing cell death inhibitors, providing a foundation for further development of these inhibitors and potential insights into the mechanisms mediating doxorubicin toxicity in patients.
Hao Siyuan S, Habib Ariful A, Zhang Xiujuan X, Ning Kang K et al.
rAAV2.5T was identified through directed evolution of an AAV capsid library in polarized human airway epithelium (HAE) cultured at an air-liquid interface (ALI). The capsid gene of rAAV2.5T is a chimera of the N-terminal unique region of AAV2 VP1 (VP1u) and the VP2 and VP3 regions of AAV5 with a single A581T substitution at the variable region (VR) VIII of the capsids. GPR108, a G protein-coupled receptor, is known as an essential host factor for the transduction of rAAV2 but not of rAAV5. Both AAV2 and AAV5 VP1u colocalized well with GPR108 and, to a lesser extent, with the trans -Golgi network (TGN). GPR108 knockout (KO) abolished rAAV2.5T transduction in both HeLa cells and HAE-ALI cultures. Remarkably, short-term treatment with doxorubicin (DOX) at 2 µM completely restored transduction, indicating that DOX can compensate for the loss of GPR108 function. DOX enhanced rAAV2.5T transduction by 50-100-fold in wild-type HAE-ALI cultures and by over 300-fold in the GPR108-deficient cultures. Mechanistic studies demonstrated that this enhancement resulted from altered intracellular trafficking that promoted efficient vector nuclear import, rather than increased vector internalization, proteasome inhibition, or activation of the DNA damage response. Importantly, we identified that the N-terminal 15 amino acids of AAV2 VP1u as the primary determinant of rAAV2.5T dependence on GPR108 for transduction. Collectively, these findings demonstrate that productive transduction of rAAV2.5T in polarized HAE cultures depends on GPR108-mediated intracellular trafficking that limits efficient nuclear entry, and that DOX can relieve this constraint by promoting efficient vector import. AAV2.5T is an airway-tropic vector with considerable promise for pulmonary gene therapy. We found that host factor GPR108 is required for rAAV2.5T trafficking from the TGN to the nucleus and that this step constitutes a major bottleneck to productive transduction in polarized HAE. In contrast, KIAA0319L (AAVR) plays a key role in AAV intracellular trafficking from the endosome to the TGN but not in internalization into polarized HAE during apical transduction. Transient treatment with low-dose doxorubicin (DOX, 2 µM) enhanced rAAV2.5T transduction in HAE by 50-100-fold through a significant increase in vector nuclear import. Notably, DOX can overcome the transduction deficit caused by GPR108 deficiency, but not that caused by AAVR deficiency. Mechanistically, the N-terminal 15 amino acids of the VP1u confer GPR108 dependence during rAAV2.5T apical transduction of polarized HAE. DOX bypasses this requirement by promoting efficient nuclear import without affecting vector internalization, inhibiting proteasomes, or inducing DNA damage response.
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