The following is a review of some of the published studies on effects of Ashwagandha  on cancer and its adjuvant role in cancer treatment. Readers should note that these studies are almost exclusively studies in animals which cannot be generalized to effects in humans without further research. It should also be noted that the dose used is generally much higher than that which is available as supplements for human use. The large number of animal studies all tend to support the conclusion that in animals ashwagandha reduces tumor cell proliferation, possibly through several mechanisms, while increasing overall animal survival time.

From the many studies published it can reasonably it can be concluded that in animals ashwagandha reduces tumor cell proliferation, possibly through multiple mecahnisms while increasing overall animal survival time. Published studies on anti-cancer effects in humans were lacking.

Devi and colleagues demonstrated a regression in sarcomas in rats treated with ashwagandha injections at doses of 500 to 750mg/ kg. ( Devi 1992)  Prakash and colleages demonstrated a reduction in DMBA induced squamous cell skin cancers in mice when treated with maximally tolerated doses of Ashwaganda for 24 weeks.(Prakash et al 2002)

Devi demonstrated that an alcoholic extract of the dried roots of Ashwagandha as well as withaferin A isolated from the extract showed significant antitumor and radiosensitizing effects  in experimental tumors in Chinese hamsters in vivo, without any noticeable systemic toxicity. (.Devi et al 1996)

 The steroidal lactone withaferin A displayed significant antitumor and radiosensitizing effects, inhibiting tumor growth and increasing survival in Swiss mice inoculated with Ehrlich ascites carcinoma (Devi et al 1995; Sharad et al 1996).

Ichikawa and colleagues investigated the anti-carcinogenic effects in animal and cell cultures by decreasing the expression of nuclear factor-kappaB, suppressing intercellular tumor necrosis factor, and potentiating apoptotic signalling in cancerous cell lines.

Yang and colleagues investigated whether Ashwagandha may be a natural proteasome ihibitor and their studies on rabbits demonstrated that the tumor proteasome 5 subunit is the primary target of Withania, and inhibition of the proteasomal chymotrypsin-like activity by Withania n vivo is responsible for, or contributes to, the antitumor effect of this ancient medicinal compound. ( Yang et al 2007)

Widodo and colleagues studied a leaf extract from Ashwagandha known as i-Extract, and found that i-Extract and its components kill cancer cells by at least five different pathways, viz. p53 signaling, GM-CFS signaling, death receptor signaling, apoptosis signaling and G2-M DNA damage regulation pathway. p53 signaling was most common. Visual analysis of p53 and mortalin staining pattern further revealed that i-Extract, fraction F1, fraction F4 and i-Factor caused an abrogation of mortalin-p53 interactions and reactivation of p53 function while the fractions F2, F3, F5 work through other mechanisms.

( Widodo et al.2008)

Padmavathi and colleagues studied the protective effects of Ashwaganda in experimentally induced skin and stomach tumours in mice. They demonstrated Ashwagandha roots inhibited phase I and activated phase II and antioxidant enzymes in the liver. Further, in a long-term tumorigenesis study,Ashwagandha inhibited benzo(a)pyrene-induced forestomach papillomagenesis, showing up to 60 and 92% inhibition in tumor incidence and multiplicity, respectively. Similarly, Withania inhibited 7,12-dimethylbenzanthracene-induced skin papillomagenesis, showing up to 45 and 71% inhibition in tumor incidence and multiplicity. In both studies, Withania showed no apparent toxic effects in mice as monitored by the body weight gain profile.(Padmavathi et al 2005)

Ashwagandha treatment significantly downregulated the gene and protein expression of proinflammatory cytokines IL-6, IL-1β, chemokine IL-8, Hsp70 and STAT-2, while a reciprocal upregulation was observed in gene and protein expression of p38 MAPK, PI3K, caspase 6, Cyclin D and c-myc. Furthermore, Ashwagandha treatment significantly modulated the JAK-STAT pathway which regulates both the apoptosis process as well as the MAP kinase signaling. These studies outline several functionally important classes of genes, which are associated with immune response, signal transduction, cell signaling, transcriptional regulation, apoptosis and cell cycle regulation and provide insight into the molecular signaling mechanisms that are modulated by Ashwagandha, thereby highlighting the use of this bioflavanoid as effective chemopreventive agent relevant to prostate cancer progression. Also demonstrated by Leyon and Kuttan, simultaneous administration of Withania extract (122 +/- 10 tumour nodules) and Withanolide (126 +/- 9 lung tumour nodules) could significantly (p < 0.001) inhibit the metastatic colony formation of the melanoma in lungs of mice..( Leyon and Kuttan)

 Ashwagandha root extract enhanced the levels of Interferon gamma (IFN-gamma) (75.87 pg/ml), Interleukin-2 (IL-2) (14.16 pg/ml) and Granulocyte macrophage colony stimulating factor (GM-CSF) (49.22 pg/ml) in normal Balb/c mice. (Davis and Kuttan 1999)

 Ashwagandha has also been studied as an adjuvant agent in minimizing adverse effects associated with anti-cancer agent cyclophosphamide:.

 Administration of Ashwagandha extract (Solanaceae) was found to significantly reduce leucopenia(low white cell count) induced by cyclophosphamide  treatment. The total WBC count on the 12th day of the cyclophosphamide-treated group was 3720 cells/mm3 and that of cyclophosphamide along with Ashwagandha was 6120 cells/mm3. Treatment of Withania along with cyclophosphamide was found to significantly (P < 0.001) increase the bone marrow cellularity (13.1 x 10(6) cells/femur) compared to cyclophosphamide alone treated group (8 x 10(6) cells/femur)( Davis and Kuttan 1998). Its use as an adjuvant treatment to prevent radiotherapy associated adverse effects was further studied by Khuttan.

Administration of a 75% methanolic extract of the plant was found to significantly increase the total WBC count in normal Balb/c mice and reduce the leucopenia induced by sublethal dose of gamma radiation. Administration of an extract from the powdered root of the plant Ashwagandha  enhanced the levels of Interferon gamma (IFN-gamma) (75.87 pg/ml), Interleukin-2 (IL-2) (14.16 pg/ml) and Granulocyte macrophage colony stimulating factor (GM-CSF) (49.22 pg/ml) in normal Balb/c mice. (Davis and Kuttan 1999) Treatment with Ashwagandha was found to increase the bone marrow cellularity significantly, the percentage increase being 146.3. Treatment with Ashwagandha had normalised the ratio of normochromatic erythrocytes and polychromatic erythrocytes in mice after the radiation exposure. Major activity of ashwagandha.  seemed to be in the stimulation of stem cell proliferation.(Khuttan 1996) In a further study the administration of Ashwagandha(20 mg/dose/animal) for five days in conjunction with cycloposphamide was associated with a reduction in urotoxicity.(  Davis and Kuttan 2000)

REFERENCES

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PU Devi, AC Sharada, FE Solomon, and MS Kamath
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J Prakash, SK Gupta, and AK Dinda
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L Davis and G Kuttan
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AC Sharada, FE Solomon, PU Devi, N Udupa, and KK Srinivasan
Acta Oncol, Jan 1996; 35(1): 95-100

10. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor- B (NF- B) activation and NF- B–regulated gene expression
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16.Effect of Withania somnifera on cytokine production in normal and cyclophosphamide treated mice.
L Davis and G Kuttan
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18..Effect of Withania somnifera on cyclophosphamide-induced urotoxicity.
L Davis and G Kuttan
Cancer Lett, Jan 2000; 148(1): 9-17.