Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic due to its high efficacy and broad spectrum. The antineoplastic activity of cisplatin is mainly due to its ability to cross-link with DNA, thus blocking transcription and replication. Unfortunately, the clinical use of cisplatin is limited by its severe, dose-dependent toxic side effects. There are approximately 40 specific toxicities of cisplatin, among which nephrotoxicity is the most common one. Other common side effects include ototoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity, cardiotoxicity, and hepatotoxicity. These side effects together reduce the life quality of patients and require lowering the dosage of the drug, even stopping administration, thus weakening the treatment effect. Few effective measures exist clinically against these side effects because the exact mechanisms of various side effects from cisplatin remain still unclear. Therefore, substantial effort has been made to explore the complicated biochemical processes involved in the toxicology of cisplatin, aiming to identify effective ways to reduce or eradicate its toxicity. This review summarizes and reviews the updated advances in the toxicological research of cisplatin. We anticipate to provide insights into the understanding of the mechanisms underlying the side effects of cisplatin and designing comprehensive therapeutic strategies involving cisplatin. OVERVIEW OF CISPLATIN1.1. Chemistry of Cisplatin. Cisplatin, chemically named cis-diamminedichloroplatinum (CDDP), was synthesized by M. Peyrone in 1844 for the first time. However, this compound did not gain much scientific attention until 1965. In this year, Rosenberg found that the electrolytic product of platinum electrodes can inhibit the growth of Escherichia coli and was later characterized to be CDDP. 1 After more than 10 years of bench and preclinic research as well as clinical trials, CDDP was approved by the FDA in 1978 for clinical use as a chemotherapeutic agent with the name cisplatin. Since then, cisplatin has been used to treat various human malignancies, including ovarian cancer, cervical cancer, testicular cancer, head and neck cancer, nonsmall cell lung cancer, and many other solid tumors. 2−4 Cisplatin is centered on a platinum atom which coordinates with two chlorine atoms and two ammonia groups to form a planar quadrilateral compound. The two chlorine atoms are on the same side (Figure 1). Initially, it was widely accepted that cisplatin enters cells by passive transport. However, studies in recent years have shown that the copper transport protein CTR1 and organic cation transporters (OCTs) also play important roles in the transport of cisplatin. 5,6 Outside cells, cisplatin is not susceptible to hydrolysis due to the high concentration of chloride ions (approximately 100 mM) in blood. Once in cells, cisplatin undergoes slow hydrolysis to form the cationic monoaqua and/or diaqua complexes (Figure 1) due to a

No abstract

In response to stress conditions, autophagy activity in multicellular organisms is systemically modulated to ensure maintenance of cellular homeostasis at an organismal level. Very little is known about the intercellular signals that elicit the long-range organism-wide autophagy response. Here we showed that during Caenorhabditis elegans development, loss of cuticle annular furrow collagens elicits autophagy in the hypodermis, intestine, and muscle. The cilia of sensory neurons with cuticle-localized endings are essential for triggering this systemic response. The TGFβ-like molecule DAF-7, which is secreted in part from a specific pair of ciliated neurons, acts as a systemic factor that activates a canonical TGFβ signaling pathway in distant tissues to induce autophagy. We also showed that AAK-2/AMPK and the STAT-like protein STA-2 act differentially in different tissues for autophagy activation. Our study reveals a circuit that senses and transduces the signal from the damaged cuticle to activate systemic autophagy during animal development.