Arginine: Appropriate Dose and Delivery Environment Makes It an Anticancer Molecule

Abstract

The electrostatic attraction between the negatively charged components of cancer cells and the positively charged anticancer peptides (ACPs) is believed to play a role in selective disruption of cancer cell membrane. Since arginine (Arg), a cationic amino acid is the most prevalent in these ACPs; we hypothesized that Arg when delivered in saline environment at the pharmacological concentration could become an anticancer molecule. The effects of L-Arg and D-Arg on tumor cell lines were studied. The therapeutic ability of pharmacological doses of Arg in saving the mice from experimental tumors was also evaluated. Both the enantiomers of Arg and not the cationic amino acid L-lysine (L-Lys) or agmatine-sulphate, at 10 mM concentration caused tumor cell clumping when treated in PBS. Arg delivered in PBS (Arg- P) and not in medium (Arg-M) up to 50 mM caused extensive tumor cell membrane damage leading to its death. Arg at 150 mM and above irrespective of chirality and incubation vehicle became an effective antitumor molecule against all the four cell lines tested. L-Arg was not toxic to normal cells like erythrocytes, lymphocytes, NIH 3T3 cells when presented in PBS. Arg cured mice bearing solid tumor fibrosarcoma (FS) when delivered into the tumor either in PBS or medium and lymphosarcoma-ascitic (LSA) tumor when delivered intraperitoneally in PBS. Our studies indicate that Arg can be used for loco-regional tumor therapy with minimal damage to normal cells and the mechanism of anticancer action of Arg is not metabolically driven but through its chemical structure, dose and delivery environment.