Table 4.
Summary of findings from in vivo and in vitro pre-clinical studies evaluating the effect of d-limonene and its derivatives on breast cancer
| Author(s) | Model | Compound and dosage under investigation | Cancer type | Effect |
|---|---|---|---|---|
| Elegbede et al. 1984 [27] | Female Sprague-Dawley Rats | 1000 or 10,000 ppm d-limonene | DMBAa-induced rat mammary tumor | Inhibited mammary carcinogenesis due to increased latency; significant differences in incidence (72% reduction in tumors at 18 weeks among d-limonene fed animal); and regression of mammary tumors. |
| Elegbede et al.1986 [28] | Female (W/Fu X F344)F2 | 10% d-limonene | DMBAa-induced rat mammary tumor | Significant regression of chemically induced tumors in rats fed d-limonene (p-value 0.016). d-limonene inhibited formation of subsequent tumors (p-value < 0.025) |
| Elson et al. 1988 [29] | Female Sprague-Dawley Rats | 5% d-limonene | DMBAa-induced rat mammary tumor | Reduction of average number of rat mammary carcinomas when fed d-limonene during the initiation or during the promotion/progression stage of carcinogenesis (p < 0.05); time to appearance of first tumor extended only when d-limonene fed during initiation stage (p < 0.005). |
| Maltzman et al 1989 [30]. | Female Wistar-Furth rats | 5% d-limonene and 5% orange oil | NMUb-induced mammary tumors | Orange oil (p < 0.001) and d-limonene (p < 0.001) prevent rat NMU- induced mammary carcinomas when introduced in the promotion/progression phase. No statistical difference in effect of orange oil and limonene. |
| Crowell et al. 1992 [16] | Female Wistar-Furth rats | 1% d-limonene and 1% hydroxylated derivativesc | aDMBA-induced rat mammary tumor | No significant effect on tumor latency or multiplicity in rats receiving 1% d-limonene. Rats receiving 1% of uroterpenol and sobreol had significant increase in latency (p < 0.005 and p = 0.0001 respectively); significant decrease in tumor multiplicity in rats fed carveol (p < 0.05), uroterpenol (p < 0.025), and sobreol (p < 0.0001). |
| Haag et al. 1992 [31] | Female Wistar-Furth rats | 0, 2.5, 5, 7.5 and 10% d-limonene | DMBAa and NMUb -induced rat mammary tumor | Statically significant complete regression rate observed starting at 5% limonene dietary levels. At 10% dietary limonene level, there was a 68% (p < 0.001) and 96% (p < 0.001) complete tumor regression rate in DBMA and NMU induced rats respectively. Established minimum dose of 7.5% dietary limonene required for a significant increase in complete tumor regression. |
| Jirtle et al. 1993 [32] | Female Fischer 344 rats | 10% d-limonene | Advanced DMBAa-induced rat mammary tumor | Significant (p < 0.0001) regression in limonene fed rats (87%) compared to the control rodents (7%). Observed increased Growth Factor β1 and Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor in limonene treated tumors, suggesting this as a possible mode of action. |
| Haag and Gould 1994 [15] | Female Wistar-Furth rats | 2% Perillyl alcohol | DMBAa-induced rat mammary tumor | Statistically significant difference (p < 0.01) in complete regression of primary carcinomas (≥ 3 mm in diameter) of perillyl alcohol fed (2.5% w/w) rats (81% and the controls 31%). Treatment group also had lower rates of secondary tumors. |
| Chander et al. 1994 [33] | Female Ludwig/Wistar/Olac rats | 10% limonene; 5% d-limonene; 12.5 mg/kg HADd; and combination 5% d-limonene and 12.5 mg/kg HADd | NMUb-induced mammary tumors | Significant rates of regression (p < 0.05) observed with 10% limonene; and 5% limonene, 4-HAD (12.5 mg/kg). Highest rate of tumor regression recorded in rats treated with the combination of 5% limonene and 4-HAD |
| Asamoto et al. 2002 [34] | Female Hras128e rats | 5% d-limonene | bNMU-induced mammary tumors | Significant reduction in multiplicity and tumor size (diameter p < 0.002, and volume p < 008) observed in rats treated with 5% d-limonene |
| Yuri et al. 2004 [35] |
In vitro: ERf+ and ERf- human breast cancer cell lines In vivo: female BALB/c mice |
500 μ M Perillyl alcohol for in vivo experiments; and 75 mg/Kg for in vitro studies | Human breast cancer cell inoculated mice | In vivo experiments: cell growth and proliferation inhibited by perillyl alcohol; In vitro study: treatment with perillyl alcohol resulted in significantly smaller tumors (p < 0.05) in terms of volume and weight |
aDMBA – 7,12-Dimethylbenz[a]anthracene
bNMU- N -methyl- N -nitrosourea
c Carveol, uroterpenol and sobrerol
d4-hydroxyandrostenedione
eHuman c-Ha-ras proto-oncogene
fEstrogen receptor