Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation.
Cancer Sci
; 113(9): 2974-2985, 2022 Sep.
Article
em En
| MEDLINE
| ID: mdl-35722994
ABSTRACT
Lactate accumulation in the tumor microenvironment was shown to be closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase A (LDHA) has been pursued as a potential novel antitumor strategy. However, only a few potent LDHA inhibitors have been developed and most of them did not show potent antitumor effects in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05. ML-05 inhibited cellular lactate production and tumor cell proliferation, which was associated with inhibition of ATP production and induction of reactive oxygen species and G1 phase arrest. In a mouse B16F10 melanoma model, intratumoral injection of ML-05 significantly reduced lactate production, inhibited tumor growth, and released antitumor immune response of T cell subsets (Th1 and GMZB+ CD8 T cells) in the tumor microenvironment. Moreover, ML-05 treatment combined with programmed cell death-1 Ab or stimulator of interferon genes protein (STING) could sensitize the antitumor activity in B16F10 melanoma model. Collectively, we developed a novel potent LDHA inhibitor, ML-05, that elicited profound antitumor activity when injected locally, and was associated with the activation of antitumor immunity. In addition, ML-05 could sensitize immunotherapies, which suggests great translational value.
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MEDLINE
Assunto principal:
Inibidores Enzimáticos
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L-Lactato Desidrogenase
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Melanoma
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Antineoplásicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article