Arginine: Appropriate Dose and Delivery Environment Makes It an Anticancer Molecule~!2009-11-16~!2009-04-15~!2010-05-05~!

Abstract

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.

Administering the Optimum Dose of l-Arginine in Regional Tumor Therapy

“…Such mechanism of the anticancer effect of the Arg is not metabolically driven but through its chemical structure which has been supported and confirmed through each of the presented efficient model to describe the energy yield by L-Arg dose and the NO assay. In the presented NO assay, LSA tumor cells treated with 10 mM of Arg in PBS environment does not produce NO in the supernatant, whereas all doses of Arg in PBS less than 50 mM damage the tumor cell membrane in the cell proliferation assay [16]. These findings confirm that the anticancer effect of the CMD observed was through a non metabolic process and that Arg pathway via the enzyme NOs does not seem to contribute to the anticancer effect of Arg through its chemical structure, i.e., was due to the strong binding of the electrostatic attraction between the negatively charged components of cancer cells and the positively charged ACPs contained in Arg.…”

“…In-Vitro Staging of Normal and Tumor Cell Lines Treated with L-Arg As conducted and described by Shukla et al [16]; normal cells of human, murine erythrocytes, murine splenic lymphocytes, NIH 3T3 cell lines and lymphosarcoma ascites (LSA) and fibrosarcoma (FS) are tumors of Swiss mouse origin and have been described earlier [17,18]. Tumor cell lines FS and LSA were cultured in RPMI-1640 medium, while NIH 3T3 was cultured in DMEM medium.…”

“…As conducted and described by Shukla et al [16]; single cell suspension of the FS cells were prepared as reported earlier and injected subcutaneously at ventro-lateral position of mice on day 0 [18]. FS therapy was initiated on day 7, post tumor transplantation when the average tumor diameter was 4.5-5.6 mm.…”

Arginine–chitosan- and arginine–polyethylene glycol-conjugated superparamagnetic nanoparticles: Preparation, cytotoxicity and controlled-release

“…This result may be due to the small size of the MNPs and the positive zeta potentials of the nanocomposites, which facilitate their entry and the release of the drug into the cells. Free Arg demonstrated a cytotoxic effect toward MCF-7 cells with an IC 50 value of 12.8 mM (2229.8 µg/mL), 27 whereas the Arg was released from the Arg–CS–MNP and Arg–PEG–MNP nanocomposites with IC 50 values of 48.6 and 42.6 µg/mL, respectively. Therefore, delivery by the nanocomposites is 46 times more effective than administration of free Arg.…”

“…26 Arginine may improve blood flow in the coronary arteries and exhibits anticancer properties against lymphosarcoma ascites, fibrosarcoma, human lung carcinoma, and human breast adenocarcinoma cells when delivered in saline at concentrations of at least 150 mM. 27…”