Neem (Azadirachta indica), a member of the Meliaceae family, is a fast growing, sturdy, and oblique leaved tropical evergreen tree. It is therefore, referred to as the "village pharmacy" in its native India. All parts of the neem tree can be used such as the fruit, seeds, bark, oil, roots, and leaves. They contain compounds known as alkaloids and limonoids, which have proven antiseptic, antiviral, antipyretic, anti-inflammatory, anti-ulcer, anti-malarial and antifungal uses. Neem contains multiple active compounds that work simultaneously via different mechanisms. One of these documented mechanisms is apoptosis (programmed cell death), which directly kills cancer cells and, in so doing, frees material from these cells that enables immune system cells to take over identifying and destroying them as well, a process called 'cross-priming'. Neem has also been shown to produce substantially higher levels of antioxidants, including the carcinogen-detoxifying enzyme glutathione. Perhaps the most important and least surprising is neem's strengthening impact on the immune system. And neem, or isolated compounds, have shown impressive efficacy against a wide variety of human cancer cell lines, and animal models for human cancers that include colon, stomach, Ehrlich's carcinoma, lung, liver, skin, oral, prostate, and breast cancers.

Neem works against carcinogens
It is well known to everybody that neem has great potentiality in inhibition of cancer development. One of the reasons behind it may the counter-effect of neem where it detoxifies carcinogens. O6-alkylguanines are potently mutagenic and pro-carcinogenic, which induces cytotoxic lesions. A facilitated elimination of these lesions by increasing the activity of O6-methylguanine-DNA methyltransferase (MGMT) is likely to be a beneficial chemoprevention strategy. A marginal enhancement of this protein may be adequate for genomic protection. Both the ethanolic and aqueous extracts from neem (Azadirachta indica) increase the levels of MGMT protein and its demethylation activity in a time-dependent manner. The herbal treatments also increased glutathione S-transferase-pi (GSTP1) expression, albeit to a lesser extent than MGMT (Niture et al., 2006). Thus, neem can be used to prevent cancer by detoxifying carcinogens like O6-alkylguanines.

Neem shows cancer protective activity
Sometimes, neem exhibits its effect in cancer protection by diiferent chemicals present in its various parts. Azadirachtin and nimbolide inhibited the development of DMBA-induced HBP carcinomas by influencing multiple mechanisms including prevention of procarcinogen activation and oxidative DNA damage, upregulation of antioxidant and carcinogen detoxification enzymes and inhibition of tumour invasion and angiogenesis (Priyadarsini et al., 2009). Nanduri et al. (2003) evaluated in vivo antitumor activity of Azadirone in modified hollow fiber animal models. The AAILE treatment reduced oxidative stress by decreasing lipid peroxidation levels and enhancing the reduced glutathione contents and activities of various antioxidant enzymes (Koul et al., 2006).

Neem Arrests tumour Cell growth and Proliferation
An extract of Neem leaves to prevent the adhesion of cancer cells to other cells in the body. Injections of Neem extract around tumors showed remarkable reduction in size in just a few weeks. Nimbolide, a natural triterpenoid present in the edible parts of the neem tree (Azadirachta indica), was found to be growth-inhibitory in human colon carcinoma HT-29 cells (Roy et al., 2006). Not only neem serve its effect on cancer by inhibiting growth of tumour cell, but also it inhibits tumour cell proliferation by upregulating and downregulating different gene expression. Harish Kumar et al. (2009) suggested the potential effect of nimbolide in cancer prevention and therapy based on its antiproliferative and apoptosis inducing effects.

Neem induces apoptosis in cancer cells
Different experimental outcomes demonstrate the obvious effect of different chemicals of neem in apoptosis of cancer cells. An ethanolic extract of neem has been shown to induce cell death in prostate cancer cells (PC-3) by inducing apoptosis as evidenced by a dose-dependent increase in DNA fragmentation and a decrease in cell viability (Suresh et al., 2006). Further, their studies indicated that treatment with neem extract could decrease level of Bcl-2, which is an anti-apoptotic protein and at the same time, increased level of expression of pro-apoptotic Bax protein. So the neem extract could be potentially effective against prostate cancer treatment.

Neem exhibits Chemoprotective potentiality
Among the different potential activity, one of the most important function that neem helps in cancer is chemoprotective potentiality. Neem may exert its chemopreventive effects in the oral mucosa by modulation of lipid peroxidation, antioxidants and detoxification systems (Balasenthil et al., 1999). Neem flowers contain some chemopreventive agents capable of inhibiting aflatoxin B(1) AFB(1) and 9,10-dimethyl-1,2-benzanthracene (DMBA) induced liver and mammary gland carcinogenesis in rats. These results strongly indicate that neem flowers may have chemopreventive potential (Aruna and Sivaramakrishnan, 1990).

Neem in Immuno-modulation
Neem, perhaps works more efficiently by modulating immune response than its other activities. CTL-mediated killing of KB cells and NK-cell-mediated killing of K562 (erythroleukemic) cells in head and neck squamous cell carcinoma patients are associated with activation of these cells by Neem leaf Glycoprotein (NLGP). NLGP-induced cytotoxicity is dependent on up-regulated perforin/granzyme B expression in killer cells, which is IFN gamma dependent in T cells, but independent in NK cells (Bose et al., 2009). However, stimulation of healthy-PBMC with NLGP maintains physiological homeostasis of CXCL10 and increases IFN gamma secretion (Chakraborty et al, 2007).

Conclusion
Neem (Azadirachta indica) has been an ancient source of herbal panacea against a variety of human health problems. Still researches are exploiting the therapeutic potential of this plant through various ongoing research projects. Different experimental results show the potentiality of different parts of neem plant in inhibition of cancer development via different mechanisms. So, the scientists may modulate their cancer research on neem to make it better therapeutic solution for cancer patients. If, neem is proved unequivocally for its effect in recovery against cancer, then, it will be able to put smile on face of terming millions throughout the world. It may as well open new vistas of drug discovery and development enriching the therapeutic wealth of Neem.

References
Aruna K, Sivaramakrishnan VM.(1990). Plant products as protective agents against cancer. Indian J Exp Biol.; 28(11):1008-11.

Balasenthil S, Arivazhagan S, Ramachandran CR, Ramachandran V, Nagini S. (1999). Chemopreventive potential of neem (Azadirachta indica) on 7,12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis. J Ethnopharmacol.; 67(2):189-95.

Bose A, Chakraborty K, Sarkar K, Goswami S, Chakraborty T, Pal S, Baral R. (2009). Neem leaf glycoprotein induces perforin-mediated tumor cell killing by T and NK cells through differential regulation of IFNgamma signaling. J Immunother. 32(1):42-53.

Chakraborty K, Bose A, Pal S, Sarkar K, Goswami S, Ghosh D, Laskar S, Chattopadhyay U, Baral R. (2007). Neem leaf glycoprotein restores the impaired chemotactic activity of peripheral blood mononuclear cells from head and neck squamous cell carcinoma patients by maintaining CXCR3/CXCL10 balance. Int Immunopharmacol.; 8(2):330-40.

Harish Kumar G, Chandra Mohan KV, Jagannadha Rao A, Nagini S. (2009).Nimbolide a limonoid from Azadirachta indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells. Invest New Drugs. 27(3):246-52.

Koul A, Mukherjee N, Gangar SC. Inhibitory effects of Azadirachta indica on DMBA-induced skin carcinogenesis in Balb/c mice. Mol Cell Biochem. 2006 Feb;283(1-2):47-55.

Kumar Suresh; Suresh P. K.; Vijayababu M. R.; Arunkumar A; Arunakaran J. (2006). Anticancer effects of ethanolic neem leaf extract on prostate cancer cell line (PC-3) Journal of ethnopharmacology, 105(2), 246-250.

Nanduri S, Thunuguntla SS, Nyavanandi VK, Kasu S, Kumar PM, Ram PS, Rajagopal S, Kumar RA, Deevi DS, Rajagopalan R, Venkateswarlu A.(2003). Biological investigation and structure-activity relationship studies on azadirone from Azadirachta indica A. Juss. Bioorg Med Chem Lett.;13(22):4111-5.

Niture SK, Rao US, Srivenugopal KS. (2006). Chemopreventative strategies targeting the MGMT repair protein: augmented expression in human lymphocytes and tumor cells by ethanolic and aqueous extracts of several Indian medicinal plants. International Journal of Oncology; 29(5):1269-78.

Priyadarsini RV, Manikandan P, Kumar GH, Nagini S. (2009). The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis. Free Radic Res. 43(5):492-504.

Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Tsushida T. (2006). Inhibition of colon cancer (HT-29) cell proliferation by a triterpenoid isolated from Azadirachta indica is accompanied by cell cycle arrest and up-regulation of p21. Planta Med. 72(10):917-23.

About Author / Additional Info:
Rajkumar Paul
Asst. Professor
Department of Biotechnology
Anand Engineering College
Agra-Mathura Road
Keetham, Agra-282007