Gambogic Acid and Inhibition of Tumor Growth: A Close Association

Dear Editor:

Gambogic acid (GA) may attenuate tumor growth in a number of other malignancies besides gastric carcinomas. ¹

For instance, similar effects are seen in mammary malignancies. GA downregulates Bcl-2 and thereby augments intratumoral apoptosis. ² These effects are time dependent. Matrix metalloproteinase (MMP)-2 and MMP-9 activity is also markedly reduced. ³ ERK1/2 phosphorylation is also attenuated. Marked elevation in p53 levels is noticed after GA administration. ⁴ Inhibition of JNK phosphorylation also accompanies the above changes and further reduces tumor growth. Chen et al. have recently demonstrated that GA results in depolymerization of microtubules resulting in reduced proliferation. ⁵ Increased G2/M phase arrest is typically seen.

GA also attenuates tumor growth in nonsmall cell lung cancers. It augments apoptosis within the pulmonary malignancies. Cells that have a greater expression of transferrin receptors are more sensitive to GA-induced metastasis. ⁶ These effects are time dependent. Bax is involved in GA-mediated apoptosis as is caspase-9. It also decreases telomerase activity within the cancerous cells. ⁷ hTERT activity is also attenuated resulting in further inhibition of tumor growth. Similar effects are seen in prostate malignancies. Lu et al. have recently demonstrated that GA has a negative impact on the NF-κB pathway, thus attenuating tumor invasiveness. Snail expression is also attenuated. ⁸ It also decreases tumor necrosis factor-α-mediated activation of the PI3K/Akt pathway, thus further contributing to the attenuation of tumor invasiveness in prostate cancers.

Wang et al. have recently shown that GA mitigates tumor growth in pancreatic carcinomas. It mediates its antineoplastic effect by attenuating ETS1 activation. ⁹ As a result, there is downregulation of vascular endothelial growth factor and cyclin D1. As a result, cancer cell migration is significantly decreased. u-PA levels are also decreased. Similar effects are seen in hepatocellular carcinomas. GA modulates stathmin 1 function and thereby accentuates intratumoral apoptosis. ¹⁰ 14-3-3 protein sigma levels are also downregulated.

The above examples clearly illustrate the significant antineoplastic effects of GA and the need for further research in this regard.