Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.

๐Ÿ‘ค Authors: Aneesha Dasgupta, Rebecca E Schmitt, Tatsuyoshi Kono, Chih-Chun Lee, Mark I Zoberi, Savannah A Epstein, Jessica Z Schneider, Alejandro Hernandez, Paul M Grandgenett, Thomas C Caffrey, Dominick J DiMaio, Michael A Hollingsworth, Jason D Doles

ABSTRACT:

Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at โˆผ80%.

Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice.

We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by ฮฑ-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.

Jason D Doles

Biochemistry - Palliative Medicine

Mayo Clinic (United States, Rochester)

United States

205

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Main topics

Publications Clinical Trials

Cancer-associated cachexia
Cachexia
Weight Loss
Pancreatic Neoplasms
Pancreatic Diseases
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