Carboplatin: molecular mechanisms of action associated with chemoresistance

Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

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Cyclin Dependent Kinase as a Novel Therapeutic Target: An Endless Story

Current Chemical Biology ◽

10.2174/2212796814999201123194016 ◽

2020 ◽

Vol 14 ◽

Author(s):

Ahmed Mohamed Etman ◽

Sherif Sabry Abdel Mageed ◽

Mohamed Ahmed Ali ◽

Mahmoud Abd El Monem El Hassab

Keyword(s):

Molecular Mechanisms ◽

Binding Pocket ◽

Structural Features ◽

Rational Drug Design ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinases ◽

Therapeutic Class ◽

Pharmacological Targets ◽

Rational Drug ◽

Cycle Regulation

Abstract:: Cyclin Dependent Kinases (CDKs) are a family of enzymes that along with their Cyclin partners play a crucial role in cell cycle regulation at many biological functions such as proliferation, differentiation, DNA repair and apoptosis. Thus, they are tightly regulated by a vast of inhibitory and activating enzymes. Deregulation of these kinases’ activity either by amplification, overexpression or mutation of CDKs or Cyclins leads to uncontrolled proliferation of cancer cells. Hyperactivity of these kinases has been reported in wide variety of human cancers. Hence, CDKs has been established as one of the most attractive pharmacological targets in the development of promising anticancer drugs. The elucidated structural features and the well characterized molecular mechanisms of CDKs have been the guide in designing inhibitors to these kinases. Yet they remain a challenging therapeutic class as they share conserved structure similarity in their active site. Several inhibitors have been discovered from natural sources or identified through high through put screening and rational drug design approaches. Most of these inhibitors target the ATP binding pocket, so they suffer from many limitations. Now a growing number of ATP non-competitive peptides and small molecules have been reported.

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Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms21155262 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5262 ◽

Cited By ~ 1

Author(s):

Qingxin Li ◽

CongBao Kang

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Structural Biology ◽

Small Molecule ◽

Molecular Interactions ◽

Mechanisms Of Action ◽

Rational Drug Design ◽

Binding Modes ◽

Small Molecule Drugs ◽

Rational Drug

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

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Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

Journal of Personalized Medicine ◽

10.3390/jpm11111185 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1185

Author(s):

Matteo Costacurta ◽

Jackson He ◽

Philip E. Thompson ◽

Jake Shortt

Keyword(s):

Multiple Myeloma ◽

Small Molecules ◽

Molecular Mechanisms ◽

Rational Drug Design ◽

Genome Wide ◽

Rational Drug ◽

Anti Cancer ◽

Cellular Machinery ◽

Endogenous Substrates ◽

New Generation

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.

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Anticipating mechanisms of resistance to PI3K inhibition in breast cancer: a challenge in the era of precision medicine

Biochemical Society Transactions ◽

10.1042/bst20140034 ◽

2014 ◽

Vol 42 (4) ◽

pp. 733-741 ◽

Cited By ~ 7

Author(s):

Cedric Leroy ◽

Romain J. Amante ◽

Mohamed Bentires-Alj

Keyword(s):

Breast Cancer ◽

Tyrosine Kinases ◽

Molecular Mechanisms ◽

Pik3ca Mutation ◽

Mechanisms Of Resistance ◽

Combination Treatments ◽

Development Of Resistance ◽

Pi3k Inhibition ◽

Pi3k Signalling ◽

Phosphoinositide 3 Kinase

Frequent subversion of the PI3K (phosphoinositide 3-kinase) pathway during neoplastic transformation contributes to several hallmarks of cancer that result in a competitive advantage for cancer cells. Deregulation of this pathway can be the result of genomic alterations such as PIK3CA mutation, PTEN (phosphatase and tensin homologue deleted on chromosome 10) loss or the activation of upstream protein tyrosine kinases. Not surprisingly, the PI3K signalling pathway has become an attractive therapeutic target, and numerous inhibitors are in clinical trials. Unfortunately, current therapies for advanced cancers that target PI3K often lead to the development of resistance and relapse of the disease. It is therefore important to establish the molecular mechanisms of resistance to PI3K-targeted therapy. With the focus on breast cancer, in the present article, we summarize the different ways of targeting PI3K, review potential mechanisms of resistance to PI3K inhibition and discuss the rationale of combination treatments to reach a balance between efficacy and toxicity.

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The role of NOTCH1 signaling in T-ALL

Hematology ◽

10.1182/asheducation-2009.1.353 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 353-361 ◽

Cited By ~ 108

Author(s):

Adolfo A. Ferrando

Keyword(s):

Molecular Mechanisms ◽

Notch Signaling Pathway ◽

Therapeutic Strategies ◽

Mechanisms Of Action ◽

Leukemic Cells ◽

Combination Therapies ◽

Activating Mutations ◽

Notch1 Signaling ◽

Major Interest

AbstractThe identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule γ-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.

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Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview

Endocrine Related Cancer ◽

10.1530/erc-20-0272 ◽

2020 ◽

Author(s):

Eliot B Blatt ◽

Noa Kopplin ◽

Shourya Kumar ◽

Ping Mu ◽

Suzanne D Conzen ◽

...

Keyword(s):

Endocrine Therapy ◽

Nuclear Receptors ◽

Therapy Resistance ◽

Therapeutic Strategies ◽

Antiestrogen Resistance ◽

Mechanisms Of Resistance ◽

Endocrine Therapy Resistance ◽

Prostate Cancers ◽

Tumor Types ◽

Compare And Contrast

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.

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microRNAs: Are they Important in the Development of Resistance in Leishmaniasis?

10.5772/intechopen.101514 ◽

2021 ◽

Author(s):

Sandra Alves de Araújo ◽

Tatiane Aranha da Penha-Silva ◽

Jaqueline Diniz Pinho ◽

Marcelo de Souza Andrade ◽

Ana Lucia Abreu-Silva

Keyword(s):

Public Health ◽

Immune Response ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Parasitic Disease ◽

Development Of Resistance ◽

Leishmania Spp ◽

Antileishmanial Drug ◽

Molecular Bases

Leishmaniasis is an infectious and parasitic disease of great importance in public health. Numerous studies indicate that biochemical and molecular mechanisms are factors that contribute to the emergence of antileishmanial drug resistance. Currently, miRNAs have been identified as targets for the invasion of pathogens to control the immune response and imply resistance to treatments. Considering the alarming growth in drug resistance, new possibilities for controlling leishmaniasis have been emerging. Natural compounds originating from medicinal plants are being increasingly explored as promising antileishmanial alternatives. The chapter aims to provide a brief review on mechanisms of action associated with traditional agents used to treat leishmaniasis, focusing mainly on molecular bases associated with the resistance of Leishmania spp. to current drugs and identifying the possible miRNAs involved in this process. In addition, we seek to describe some of the promising plant molecules that can be used as potential antileishmanial agents and their possible mechanisms of action.

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