The lysosome among targets of metformin: new anti-inflammatory uses for an old drug?

Abstract

Background: Rheumatoid arthritis and type-2 diabetes exhibit progressive co-morbidity. Chloroquine (CQ) reportedly improves both. CQ inhibits lysosomal function in cultured cells at supra-therapeutic concentration; however, this is doubted as target mechanism. Some anti-diabetic biguanides are metal-interactive lysosomal inhibitors; and all bind Zn²⁺.

Objectives: i) To bioassay the potency of CQ using ³H-leucine release from perfused myocardial tissue. ii) To determine whether metformin (MET) is CQ-mimetic, and interactive with Zn²⁺.

Results: Therapeutic CQ concentration (0.1 – 0.5 μM) clearly does cause lysosomal inhibition although delayed and submaximal. MET alone (10 μM) caused sub-maximal inhibition. Supra-physiological extracellular Zn²⁺ (5 – 50 μM) alone increased tissue Zn²⁺ content, and inhibited lysosomal proteolysis. Physiological equivalent Zn²⁺ (approximately 1 μM) had no effect. MET (≤ 25 μM) and Zn²⁺ (≤ 1 μM) exhibited astounding 10 – 100 fold anti-lysosomal synergy. Cathepsin B was 50% inhibited by 1 μM Zn²⁺, and is reportedly inhibited by gold agents.

Interpretation: MET somehow increases the natural inhibitory action of action of Zn²⁺ against cysteinyl proteases. TNF-alpha activates lysosomal function; and CatB is among post-receptor players. MET might decrease antigen processing in specialized cells, and lysosomal hyper-catabolism in other cells.

Conclusions: Trials of MET for new use as an anti-inflammatory agent are suggested. Guanidylguanidine is a practical pharmacophore for synthesis of future anti-lysosomal agents.

Keywords::

• cathepsin B
• chloroquine
• diabetes
• inflammation
• lysosome
• metformin
• nano-pharmacology
• zinc

Acknowledgement:

Dr David Thorne, Department. of Medical Technology, Michigan State University is gratefully acknowledged for Zn measurements.