Since oxidative stress is one of the known sources of endoplasmic reticulum stress, we investigated whether PLD was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Plitidepsin binds to eEF1A2 and induces oxidative stress, Rac1 activation and JNK1 phosphorylation, triggering a rapid apoptotic program in tumor cells. Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory authorities for the treatment of multiple myeloma patients. We also review its design, pharmaceutical data, and mechanism of action. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications.
CARLOS GAVAZZI PDI 40 TRIAL
In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents.
Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. We herein highlight the main enzymatic pathways targeted by marine-derived clinical agents, predominantly and/or partially contributing to the associated pharmacological effects. The large increase in the number of clinical candidates directly derived or inspired by marine lead structures turns the marine-derived pipeline not only dynamic, but most of all promising. Currently, the global clinical arsenal comprises six approved drugs in addition to more than 20 candidates in clinical development. Notably, most of the marine-derived chemical entities available for clinical use and/or that progressed to clinical development were found to exert their pharmacological effects by interfering with a plethora of enzymes, either through a direct targeting effect or by altering their expression. To date, over 25,700 new compounds have been reported from marine organisms, with invertebrates prominently featuring as the top-contributing source.
The vast repertoire of structurally diverse prototype compounds with pronounced pharmacological properties discovered from marine organisms over the last five decades, has vastly contributed to the renaissance in natural product-based drug discovery. This paper addresses the significance of bioactive compounds from marine invertebrates to the development of new drugs. For these reasons, marine organisms may represent precious resources for developing drug candidates, cosmetics, nutritional supplements, and molecular probes for improving our well-being. Thus, these substances often possess meaningful pharmacological properties. Many of these chemicals affect metabolic pathways that are common to humans and are involved in critical physiological functions. Since then, these organisms have dealt successfully with competitors and predators by developing a unique arsenal of highly effective secondary metabolites for their defense, reproduction, and communication. The majority of marine organisms has an evolutionary history that dates back to the Cambrian, some 500 million years ago. More recently, the amazing biodiversity represented by the world's oceans have been realized to represent an equally and exceptionally rich source of valuable bioactive compounds. This has led to the development of life-saving drugs for treating a multitude of conditions including infectious, cardiovascular, malignant, and diabetic disease. Man has probably used since his existence plants and plant-derived compounds for his health care and well-being.
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