Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics
Abstract
:Simple Summary
Abstract
1. History of Chemotherapy
2. Conventional Chemotherapeutic Compounds and Cell Death
2.1. Antimetabolites
2.2. Alkylating Agents
2.3. Topoisomerase Inhibitors
2.4. Microtubule-Targeting Agents (Vinca Alkaloids and Taxanes)
2.5. Cell-Fate Determination Post-Chemotherapeutic Challenge through Lysosomes
3. Lysosome-Mediated Acquired Chemoresistance
3.1. Organellar Physiology of Lysosomes
3.2. The Endocytic Origin and Metabolic Signaling of Lysosomes
3.3. Lysosomal Abberations in Cancer and Chemoresistance
3.4. Lysosomal Entrapment of Weak-Base Compounds
3.5. Novel Therapeutic Strategies for Lysosome-Mediated Chemoresistance
4. Concluding Remarks
Funding
Conflicts of Interest
References
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Drug Family | Drug Class | Drug Name | Molecular Mode of Action | References |
---|---|---|---|---|
Alkylating Agents | Nitrogen mustard | N-methyl-bis(2-chloroethyl) amines, Chlorambucil, Melphalan, Cyclophosphamide | Crosslinks DNA strands through initiating nucleophilic substitution with reactive centers on N and O of DNA base substrates | [15,134] |
Temozolomide, N-methyl-N-Nitrosoguanidine, Procarbazine | Forms localized N and O-alkyl adduct on one reactive center of DNA substrates that serves as the basis for extensive genotoxic damages, including DNA double-stranded breaks and chromosomal translocation. | [17,18,19] | ||
Platinum-based alkylating agent | Cisplatin | Induces DNA intra-strand crosslinks, reactive oxygen species production, cell cycle arrest, and alterations of Ca2+ signaling | [21] | |
Antimetabolites | Purine antagonist | Mercaptopurine (6-MP) | Inhibits de novo purine synthesis Produces genotoxic thioguanine nucleotides that inhibit DNA and RNA synthesis and alter their subsequent metabolism | [7,9] |
Thymidine phophorylase inhibitor | Tipiracil Hydrochloride (TAS-102) | Induces cell cycle arrest at G2 phase and DNA double-strand breaks with enhanced drug potency. | [135,136] | |
Antifolate | Methotrexate, Pemetrexed | Depletes intracellular thymidine by inhibiting TYMS, DHFR, AICARFT, GART Increases intracellular dUMP and promotes its misincorporation into the DNA in inducing double-strand breaks. | [137,138] | |
Topoisomerase Inhibitors | Topo I inhibitor | Camptothecin | Uncompetitively cleaves DNA-topo 1 binary complex and enlarges the DNA cleavage gap, preventing further DNA re-ligation while causing collision with replication forks and eliciting apoptosis through exposure of DNA free ends. | [26,27] |
Bibenzimidazole, Terbenzimidazole | Poisons Topo I by binding to the DNA minor groove | [139] | ||
Topo II inhibitor | Doxorubicin, Daunorubicin, Idarubicin | Intercalates DNA and forms DNA covalent adducts Mediates Cell cycle arrest Generates reactive oxidative species | [28] | |
Bisdioxopiperazine | Stabilizes ATP-bound Topo II, thereby inhibiting the enzyme’s catalytic cycles | [34,35] | ||
Resveratrol | Prevents dimerization of Topo II ATPase domain, thereby allosterically inhibiting the enzyme’s catalytic cycles | [37] | ||
Microtubule-targeting Agents | Vinca alkaloid | Vincristine, Vinblastine, Vinorelbine | Inhibits microtubule polymerization Induces oxidative DNA damage | [43,45] |
Taxane | Docetaxel, Paclitaxel | Binds to and stabilizes tubulin polymers | [140] | |
Cabazitaxel | Inhibits microtubule shortening and overall dynamicity | [50,51] |
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Zhai, X.; El Hiani, Y. Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics. Cancers 2020, 12, 3669. https://doi.org/10.3390/cancers12123669
Zhai X, El Hiani Y. Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics. Cancers. 2020; 12(12):3669. https://doi.org/10.3390/cancers12123669
Chicago/Turabian StyleZhai, Xingjian, and Yassine El Hiani. 2020. "Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics" Cancers 12, no. 12: 3669. https://doi.org/10.3390/cancers12123669