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1.
Toxicol Appl Pharmacol ; 421: 115534, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33852878

RESUMO

Monomethyl auristatin E (MMAE) is a potent anti-cancer microtubule-targeting agent (MTA) used as a payload in three approved MMAE-containing antibody drug conjugates (ADCs) and multiple ADCs in clinical development to treat different types of cancers. Unfortunately, MMAE-ADCs can induce peripheral neuropathy, a frequent adverse event leading to treatment dose reduction or discontinuation and subsequent clinical termination of many MMAE-ADCs. MMAE-ADC-induced peripheral neuropathy is attributed to non-specific uptake of the ADC in peripheral nerves and release of MMAE, disrupting microtubules (MTs) and causing neurodegeneration. However, molecular mechanisms underlying MMAE and MMAE-ADC effects on MTs remain unclear. Here, we characterized MMAE-tubulin/MT interactions in reconstituted in vitro soluble tubulin or MT systems and evaluated MMAE and vcMMAE-ADCs in cultured human MCF7 cells. MMAE bound to soluble tubulin heterodimers with a maximum stoichiometry of ~1:1, bound abundantly along the length of pre-assembled MTs and with high affinity at MT ends, introduced structural defects, suppressed MT dynamics, and reduced the kinetics and extent of MT assembly while promoting tubulin ring formation. In cells, MMAE and MMAE-ADC (via nonspecific uptake) suppressed proliferation, mitosis and MT dynamics, and disrupted the MT network. Comparing MMAE action to other MTAs supports the hypothesis that peripheral neuropathy severity is determined by the precise mechanism(s) of each individual drug-MT interaction (location of binding, affinity, effects on morphology and dynamics). This work demonstrates that MMAE binds extensively to tubulin and MTs and causes severe MT dysregulation, providing convincing evidence that MMAE-mediated inhibition of MT-dependent axonal transport leads to severe peripheral neuropathy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Oligopeptídeos/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Sistema Nervoso Periférico/efeitos dos fármacos , Moduladores de Tubulina/toxicidade , Tubulina (Proteína)/metabolismo , Transporte Axonal/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Microtúbulos/metabolismo , Microtúbulos/patologia , Mitose/efeitos dos fármacos , Oligopeptídeos/metabolismo , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ligação Proteica , Medição de Risco , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Fuso Acromático/patologia , Moduladores de Tubulina/metabolismo
2.
Cancer Chemother Pharmacol ; 76(5): 1013-24, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26416565

RESUMO

Ixabepilone (Ixempra, BMS-247550), a semisynthetic analog of epothilone B, is a microtubule-targeted drug in clinical use for treatment of metastatic or locally advanced breast cancer. Ixabepilone's binding and mechanism of action on microtubules and their dynamics, as well as its interactions with isotypically altered microtubules, both in vitro and in tumor cells, have not been described. Microtubules are dynamic polymers of the protein tubulin that function in mitosis, intracellular transport, cell proliferation, and migration. They continually undergo dynamic instability, periods of slow growth and rapid shortening that are crucial to these cell functions. We determined ixabepilone's microtubule binding and polymerization effects in vitro and also determined its effects on inhibition of dynamic instability in vitro and in cells, both with and without removal of the ßIII isotype of tubulin. The ßIII isotype of tubulin is associated with drug resistance and tumor aggressivity. We found that removal (in vitro) and knockdown (in cells) of ßIII-tubulin led to increased inhibition of microtubule dynamic instability by ixabepilone. Depletion of ßIII-tubulin from MCF7 human breast cancer cells also induced increased mitotic arrest by ixabepilone. Thus, ßIII-tubulin expression suppresses the antitumor effects of ixabepilone, indicating that increased ßIII-tubulin may be an important contributor to the development of resistance to ixabepilone.


Assuntos
Antineoplásicos/farmacologia , Epotilonas/farmacologia , Isoformas de Proteínas/fisiologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/fisiologia , Adenocarcinoma/patologia , Sequência de Aminoácidos , Animais , Química Encefálica , Neoplasias da Mama/patologia , Bovinos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Microtúbulos/efeitos dos fármacos , Estrutura Molecular , Paclitaxel/farmacologia , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Relação Estrutura-Atividade , Transfecção , Tubulina (Proteína)/química , Tubulina (Proteína)/efeitos dos fármacos
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