Cancer is a multistep process resulting in uncontrolled cell division. It results from aberrant signaling pathways that lead to uninhibited cell division and growth. Various recent epidemiological studies have indicated that consumption of cruciferous vegetables such as garden cress, broccoli, etc., reduces the risk of cancer. Isothiocyanates (ITC) have been identified as major active constituents of cruciferous vegetables. ITCs occur in plants as glucosinolate and can readily be derived by hydrolysis. Numerous mechanistic studies have demonstrated the anti-cancer effects of ITCs in various cancer types. ITCs suppress tumor growth by generating reactive oxygen species or by inducing cycle arrest leading to apoptosis. Based on the exciting outcomes of pre-clinical studies, few ITCs have advanced to the clinical phase. Available data from pre-clinical as well as available clinical studies suggests ITCs to be one of the promising anti-cancer agents available from natural sources. This is an up-to-date exhaustive review on the preventive and therapeutic effects of ITCs in cancer.

Recent studies have revealed that 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) has anti-tumorigenic activity in vitro. In the present work, we evaluated the in vitro and in vivo antiangiogenic and antitumor activities of PGG and examined its molecular mechanisms. PGG significantly inhibited the proliferation and tube formation in basic fibroblast growth factor (bFGF)-treated human umbilical vein endothelial cells (HUVECs) at non-cytotoxic concentrations. PGG effectively disrupted the bFGF-induced neo-vascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When mice were intraperitoneally injected, PGG also significantly inhibited tumor angiogenesis induced by Lewis lung carcinoma (LLC) and the growth of LLC by 57 and 91% of control tumor weight at 4 and 20 mg/kg, respectively. Immunohistochemical analysis revealed decreased microvessel density, decreased expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), reduced tumor cell proliferation and increased tumor cell apoptosis. Similarly, PGG significantly attenuated the expression of COX-2 and VEGF and reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs. Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neo-vascularization in CAM, supporting the role of COX-2 in PGG inhibition of angiogenesis. PGG diminished the phosphorylation of extracellular signal regulated kinase 1/2, Jun NH2-terminal kinase and activated phospho-p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner in bFGF-treated HUVECs. In addition, p38 inhibitor SB203580 abolished the downregulation of COX-2, VEGF and the antiproliferative activity by PGG. Taken together, our data demonstrate that PGG exerts antitumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK- dependent pathways.

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The Phellinus Linteus (PL) mushroom has been shown to possess anti-tumor properties. Through influencing lymphocytes, PL indirectly augments the host's immune system against cancer cells. PL has also been demonstrated to reduce tumor proliferation. However, the mechanisms of PL against malignant growth have not yet been fully explored. In this study, we report that PL mediates the following two activities in mouse and human lung cancer cells: cell-cycle arrest at a low concentration of PL and apoptosis in response to a high dose of PL. After exposure to a low dose of PL, G(1) growth arrest occurred in the lung cancer cells. The negative growth control mediated by PL is evidenced by the decrease of the activities of cyclin-dependent kinases CDK2, 4, and 6. In contrast, at high doses, PL-induced lung cancer cells to undergo apoptosis in a dose-dependent fashion. This was evidenced by DNA fragmentation, caspase activation, and loss of clonogenecity in the lung cancer cells, all of which were lacking in the lung cancer cells treated with low concentrations of PL as well as the normal mouse lung epithelial cells exposed to either low or high concentrations of PL. The addition of the caspase inhibitor Z-VADfmk completely suppressed PL-induced apoptosis. Furthermore, the low dose of PL was able to synergize with doxorubicin to induce apoptosis in the lung cancer cells. Thus, our findings suggest that PL regulates two responses in the lung cancer cells: cell-cycle arrest and apoptosis.

Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.