Dynasore br Lung cancer br Benzo a pyrene B a
Benzo(a)pyrene [B(a)P] is one of the most potent carcino-gens, which promotes the development and metastasis of lung cancer through inducing DNA intercalation, oxidative damage, mutations, chromosomal aberrations, and overt tumorigenesis. Wang et al. investigated whether SAMC can prevent B(a)P-induced precancerous carcinogenesis in the human lung cell
line A549. Both pre-treatment and co-treatment of SAMC significantly reversed B(a)P-induced A549 cell proliferation, ROS formation, DNA damage, NF-κB activation and Dynasore alteration in vitro, suggesting the therapeutic potential of SAMC in managing B(a)P-induced human lung cancer .
By using several established human cell lines (HO8910, HO8910PM, and SKOV3), Wu et al. investigated the effects of SAMC on ovarian cancer cells. In vivo and in vitro ex-periments showed that SAMC induced apoptosis and restored E-cadherin expression in SKOV3 and HO8910 cells, which agrees with earlier findings [28, 39]. However, HO8910PM cells, a line with high metastatic potential, showed markedly higher resistant to SAMC effect in colony formation, cells migration, invasion, and tumor growth in a xenograft mice model. Fur-ther study revealed that the survivin gene was highly ex-pressed in HO8910PM cells. Pre-treatment with specific sur-vivin siRNA resensitized HO8910PM cells to SAMC . These results suggest that downregulation of survivin expres-sion/activity in conjunction with SAMC treatment could be a possible approach to managing this malignant cancer, where survivin is highly expressed.
Studies on the anti-proliferative potential of SAMC in the erythroleukemia cell lines HEL and OCIM-1 have provided evidence that SAMC can induce dose-dependent inhibition of cell growth, G2/M phase arrest, and apoptosis initiation [26, 40]. In DS19 mouse erythroleukemia cells, SAMC (25 mmol·L−1) blunted cell proliferation and induced histone acetylation. In
further validation with Caco-2 human colon cancer cells and T-47D human breast cancer cells, SAMC also triggered his-tone acetylation, suggesting a general epigenetic response. The mechanism by which SAMC induces histone acetylation currently remains poorly understood, though it may be partially related to SAMC’s catabolic product allyl mercaptan, which can act as a competitive HDAC inhibitor to promote
rapid and sustained histone hyperacetylation in human can-cer cells .
As most malignancies are costly and far from tractable in the clinic, early prevention and management by everyday intake of food supplements with anti-cancer potential has emerged as a cogent and practicable idea in the past decades. Numerous lines of evidence in basic and clinical research have confirmed the medicinal benefits of garlic constituents in cancer prevention or treatment, including AGE-derived organosulfur compounds . The ability of SAMC to remove
ROS and up-regulate antioxidant enzymes may explain one of the main reasons to anti-cancer . Current researches pro-vide compelling evidence that SAMC possess anti-tumor property mainly through activating MAPK, scavenging active oxygen and resisting inflammation . SAMC induces Bcl-2 family imbalance to cause apoptosis of tumor cell through modulation of MAPK pathway and mitochondrial cytochrome c release. Meanwhile, SAMC also can inhibit tumor cell pro-liferation by inducing histone acetylation and inhibiting microtubule polymerization. Besides, mechanistic studies showed that SAMC induced E-cadherin to suppress tumor cell invasiveness (Fig. 3). Apart from direct anti-neoplastic
Fig. 3 Signaling pathways involved in SAMC mediated cancer inhibition
properties, SAMC has been found to increase the chemo-sensitivity of cancer cells. In a nude mice model implanted with the HRPC cell line CWR22R, combined treatment of docetaxel and SAMC yielded synergistic anti-tumor outcomes, which included reduced tumor growth, downregulation of Bcl-2 and upregulation of E-cadherin, with no obvious adverse effects. SAMC can significantly enhance the ability of rapa-mycin inducing colon cancer cell apoptosis and inhibiting tumor growth in xenograft nude mice . In another study, co-administration of sulindac sulfide (SS) with SAMC in human colon cancer cell lines (SW-480 and HT-29) led to a significantly enhanced capacity to inhibit cell proliferation and induce apoptosis, as compared with SS alone .
Indeed, there remain several research gaps in our under-standing on SAMC-mediated cancer inhibition. First, even though SAMC is considered as a novel anti-cancer candidate compound, the pharmacokinetics of SAMC is unestablished. Second, potential pharmacological interactions between SAMC and other garlic-derived organosulfur compounds (e.g. SAC and allicin) are largely unclear, though some commercial AGE formulations may come as a mixture of those com-pounds. Third, the direct interacting proteins/molecular tar-gets of SAMC in cells are unknown. Whether SAMC inter-acts with membrane receptors to transduce anti-cancer signals in cancer cells remains to be clarified. Fourth, although garlic is generally safe for most people when taken appropriately via the oral route, it can elicit a number of side effects in some people, including nausea, vomiting, body odor, bleeding and diarrhea . Lastly, clinical study on the anti-cancer therapeu-tic efficacy is needed to further prove the availability of SAMC as a novel and safe drug. Thus, development of novel drug forms is critical for the safe daily use of SAMC or AGE in preventing or managing cancer.