Piperine: Immunomodulatory and antitumor effects

Piperine: A pungent alkaloid that is concentrated in the outer skin of pepper berries (which gives pepper much of its bite) and is found in other spices and vegetables including jalapeno peppers. Piperine is used as a flavoring and as an insecticide. The word is derived from the Latin piper, pepper.Piper longum Linn., an important medicinal plant, is used in traditional medicine by many people in Asia and Pacific islands especially in Indian medicine (Guido et al., 1998).

Piper longum is a component of medicines reported as good remedy for treating gonorrhea, menstrual pain, tuberculosis, sleeping problems, respiratory tract infections, chronic gut related pain, and arthritic conditions (Singh, 1992). Other reported beneficial effects of Piper longum include analgesic and diuretic effects, relaxation of muscle tension, and alleviation of anxiety (Singh and Blue Menthal, 1997). Piperine was the first amide isolated from piper species and was reported to display central nervous system depression, antipyretic, and anti-inflammatory activity (Virinder et al., 1997). Piperine is a potent inhibitor of the mixed function oxygenase system and non-specific inhibition of P450 isoenzymes (Atal et al., 1985). Constituents of piper species have inhibitory activity on prostaglandin and leukotriene biosynthesis in vitro (Stohr et al., 2001). However, no study on the immunomodulatory and antitumor activity of Piper longum and piperine has been reported. In order to verify the anecdotal claims that Piper longum and piperine has numerous phytochemical benefits, we have investigated the immunomodulatory and antitumor activities of the plant and its derivative.

The main objective of this study was to focus on the immunomodulatory and antitumor activity of alcoholic extract of Piper longum and its component piperine. Immunoregulation is a complex balance between regulatory and effector cells, and any imbalance in immunological mechanism can lead to pathogenesis (Steven et al., 1985). Immunosuppression is one of the main obstacles in the conventional cancer treatment such as chemo- and radiotherapy.

Presently different types of immunomodulators are available. Depending upon their sources they can be divided into natural and synthetic immunomodulators. These can alleviate the side effects, which is the major problems in other conventional therapies.

There are reports that extracts from plants, such as Viscum album (Kuttan and Kuttan, 1992), Withania somnifera (Davis and Kuttan, 2000), Tinospora cordifolia (Mathew and Kuttan, 1999), etc., could stimulate the immunity in natural as well as tumor bearing animals. They have also shown to alleviate the immunosuppression induced by chemo- and radiotherapy (Praveen Kumar et al., 1999). We already reported that the piperine could inhibit the metastasis induced by B16F10 melanoma cells (Pradeep and Kuttan, 2002).

The dosage of Piper longum extract and piperine was selected on the basis of cytotoxicity. 10 mg/dose/animal for Piper longum extract and 1.14 mg/dose/animal for piperine is the lowest concentration with maximum activity. Administration of Piper longum extract and piperine showed increased number of total WBC count. This indicates they can stimulate the hemopoietic system. The differential count shows the drug did not alter the ratio of different WBC types.

Bone marrow serves as the major source of all blood cells, including lymphocytes. Administration of Piper longum extract and piperine showed an increase in bone marrow cellularity and α-esterase positive cells indicating its effect on stem cell proliferation.

Extract of Piper longum and piperine was found to increase the circulating antibody titer and antibody forming cells indicating its stimulatory effect on the humoral arm of immune system. Administration of this drug could also significantly inhibit the growth of solid tumor induced by DLA cells and ascites tumor induced by EAC cells.

Immunomodulators may activate cytotoxic effector cells, such as cytotoxic T lymphocytes, natural killer (NK) lymphocytes, macrophages, and activated neutrophils (Fidler and Poste, 1985). Use of chemotherapy plus target-specific immunomodulators hold a reasonable promise for clinical utility in future.

Immunomodulatory activity of Piper longum and piperine may be due to the combined action of humoral and cell-mediated immune responses. Hence, the results indicated that the Piper longum and piperine could act as a non-toxic immunomodulator which posses antitumor property also. The exact mechanism of action responsible for the tumor reducing activity has to be studied further.