Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death

Nuzzo, Genoveffa; Gallo, Carmela; Crocetta, Fabio; Romano, Lucia; Barra, Giusi; Senese, Giuseppina; Dell'isola, M.; Carbone, Dalila; Tanduo, Valentina; Albiani, Federica; Villani, Guido; d’Ippolito, Giuliana; Manzo, Emiliano; Fontana, Angelo

doi:10.3390/biom12020246

Cited by 11 publications

(13 citation statements)

References 49 publications

(76 reference statements)

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“…Lately, we have identified by bioassay-guided fractionation the alkaloid lepadin A (45) from the tunicate Clavelina lepadiformis sp. B, already known to exhibit significant in vitro cytotoxicity against several human cancer cell lines, as a potent activator of innate immune cells [189]. In this study, lepadin A showed both cytotoxic effect against chronic forms of lung carcinoma, melanoma, and multiple myeloma cells together with maturation of mouse dendritic cells at micromolar concentrations.…”

Section: Compounds From Marine Environmentmentioning

confidence: 49%

“…Moreover, the immune response of 45 occurs at subtoxic concentrations (EC 50 = 1.64 µg/mL; IC 50 = 4.20 µg/mL), indicating that the molecule can induce a cell stress. On this basis, even though further studies are needed to investigate the mechanism of action, it was suggested that lepadin A could act as ICD inducer [189].…”

Section: Compounds From Marine Environmentmentioning

confidence: 99%

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Antitumor Potential of Immunomodulatory Natural Products

Nuzzo¹,

Senese²,

Gallo³

et al. 2022

Marine Drugs

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Cancer is one of the leading causes of death globally. Anticancer drugs aim to block tumor growth by killing cancerous cells in order to prevent tumor progression and metastasis. Efficient anticancer drugs should also minimize general toxicity towards organs and healthy cells. Tumor growth can also be successfully restrained by targeting and modulating immune response. Cancer immunotherapy is assuming a growing relevance in the fight against cancer and has recently aroused much interest for its wider safety and the capability to complement conventional chemotherapeutic approaches. Natural products are a traditional source of molecules with relevant potential in the pharmacological field. The huge structural diversity of metabolites with low molecular weight (small molecules) from terrestrial and marine organisms has provided lead compounds for the discovery of many modern anticancer drugs. Many natural products combine chemo-protective and immunomodulant activity, thus offering the potential to be used alone or in association with conventional cancer therapy. In this review, we report the natural products known to possess antitumor properties by interaction with immune system, as well as discuss the possible immunomodulatory mechanisms of these molecules.

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Section: Compounds From Marine Environmentmentioning

confidence: 49%

Section: Compounds From Marine Environmentmentioning

confidence: 99%

Antitumor Potential of Immunomodulatory Natural Products

Nuzzo¹,

Senese²,

Gallo³

et al. 2022

Marine Drugs

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“…These preliminary results of biological activities suggest a great potential for developing lepadins as a new class of medicines. However, the in-depth investigation of the biological functions of lepadins, in particular, their mechanism of action, remains rare and challenging, , partially due to the unavailability of these rare marine natural products. To address the supply of materials, we have developed a novel synthetic strategy for the efficient construction of the highly functionalized cis -fused DHQ core on multigram scale, which led to a collective total synthesis of seven members of lepadins (Supporting Information Figure S1) .…”

Section: Discussionmentioning

confidence: 99%

“…It was noted that lepadin A was previously reported to be cytotoxic against cancer cells with maturation of mouse dendritic cells at micromolar concentrations. 62 The combination of these two effects is expected to improve anticancer efficacy through a synergistic mechanism derived from both the role of mature dendritic cells in the generation of anti-tumor activity and the release of immunogenic molecules by dying cells. Unfortunately, at this moment, we were not able to in vivo study the immunogenic response of lepadin H.…”

Section: Discussionmentioning

confidence: 99%

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Wang,

Ma,

Cheung

et al. 2023

J. Med. Chem.

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Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

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“…Starting from the development of an innovative screening platform for the identification of immunomodulatory compounds [ 16 ], we have recently reported that lepadin A ( 1 ) shows a cytotoxic effect in a panel of cancer cell lines along with the ability to induce maturation of mouse dendritic cells (DCs). The combination of this activity led us to put forward a potential role as ICD inducer for this natural product [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway

Carbone,

Gallo,

Nuzzo

et al. 2023

Nat. Prod. Bioprospect.

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Immunogenic Cell Death (ICD) represents a mechanism of enhancing T cell-driven response against tumor cells. The process is enabled by release of damage-associated molecular patterns (DAMPs) and cytokines by dying cells. Based on molecular studies and clinical marker assessment, ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs. In view of the development of small molecules in targeted cancer therapy, we reported the preliminary evidence on the role of the natural product lepadin A (1) as a novel ICD inducer. Here we describe the ICD mechanism of lepadin A (1) by proving the translocation of the protein calreticulin (CRT) to the plasma membrane of human A2058 melanoma cells. CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A (1). After the treatment, the tumour cells acquired the ability to activate dendritic cells (DCs) with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism. The effect of lepadin A (1) was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin (2), a well-established ICD inducer.

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Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death

Cited by 11 publications

References 49 publications

Antitumor Potential of Immunomodulatory Natural Products

Antitumor Potential of Immunomodulatory Natural Products

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway

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