• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • br reportedly involved in these processes Similarly


    reportedly involved in these processes [31, 42]. Similarly, stud-ies in SNU-1 gastric cancer cells confirmed the pro-apoptotic activities of SAMC [31]. SNU-I after treatment of SAMC showed a mitochondrial cytochrome c activation and an in 
    vitro caspase-3 activity [10]. In a nude mice model implanted with tumors of human KMN-45 gastric cancer cells, SAMC administration was found to suppress tumor growth and induce apoptosis in tumor cells via Bcl-2 family-related pathways [32].
    Table 1 Summary of anti-neoplastic mechanisms of SAMC
    Cancer type Models Treatment and dosage Proposed mechanisms Ref. Colon Cells and SW-480 and HT-29 cells treated with 300 μmol·L−1 SAMC Activation of JNK1 pathway; microtubule [5, 21-24]
    mice alone or in combination with sulindac sulfide for 24 h. SAMC depolymerization; mitochondrial mem-
    at 300 mg·kg−1·day−1 in mice by gavage feeding for 16 d. brane depolarization
    Prostate Cells and 0−200 μmol·L−1 SAMC-treated LNCaP cell or SAMC-treated
    mice PC-3, DU145 cells for 24 h. Mice were orogastrically fed of
    different doses of SAMC for 28 d.
    daily orogastric feeding for 24 d. 
    Rescue of GSH deficits; alteration of [25-30] prostate biomarker expression and testos-
    terone utilization; restoration of E-cadherin
    family-related pathways
    apoptotic protein Bcl-2 and Bcl-XL down-
    Liver Cells HepG2 cells tested with 800 μmol·L−1 SAMC alone or in combination with MAPK inhibitors for 8 h.
    Bladder Cells 0−200 μmol·L−1 SAMCtreated stable Id-1-expressing and
    Id-1 as a potential target of SAMC medi- [7] ated treatment
    mice SAMC for 2 to 8 h. Mice were given intragastric administra-
    Lung Cells A549 cells were either pre-treated or co-treated with 1 μmol·L−1
    Inhibition of ROS formation, DNA dam- [39] age, and NF-κB activation
    Erythroleu- Cells SAMC treated OCIM, HEL and DS19 cells in the dosage of Induction of histone acetylation [26, 40-41] kemia
    Colon cancer
    Among cancer types, colon cancer has been extensively studied to characterize the mechanistic roles of SAMC in cancer treatment. SAMC challenge (200 μmol·L−1) markedly inhibited cell growth, arrested G2/M gamma-Glu-Cys phases, in-duced apoptosis, and suppressed invasion of the colon cancer cell lines SW-480 and HT-29. The observed phenotypes were accompanied by activation of caspase-3 and JNK1 signaling and induced GSH upregulation [21]. Other studies also un-veiled several mechanistic pathways by which SAMC exerts its suppressive effects in colon cancer cells. Firstly, SAMC modulates normal cellular functions by altering cytoskeleton dynamics. In vitro immunofluorescence study showed that treatment of SW-480 cells or NIH3T3 fibroblasts with SAMC leads to rapid microtubule depolymerization, microtubule cytoskeleton disruption, Golgi dispersion, centrosome frag-mentation, and spindle assembly disruption in mitotic cells. While co-treated with β-mercaptoethanol (β-ME), a reducing agent with one -SH/molecule, significantly reduced the effect of SAMC on microtubule polymerization [5]. SAMC could also inhibit de novo tubulin polymerization to induce micro-
     tubule depolymerization [5]. Secondly, SAMC selectively perturbs signal transduction pathways important for stress response and control of cell death/survival. Of note, activation of JNK1 and subsequent caspase seems to be critical for PARP-mediated apoptosis, since JNK1 knockout or selective JNK inhibitor SP600125 application blocked the apoptosis induced by SAMC in the early phase (24 h) but not the late phase (48 h). Other MAPK family members, such as ERK1/2 and p38 MAPK, were found to be not involved in SAMC-induced SW-480 apoptosis. When cells were pre-treated with specific inhibitors of ERK1/2 (PD98059) or p38 MAPK (SB203580) prior to SAMC incubation in SW-480 cells at concentrations sufficient for suppressing ERK1/2 or p38 pho-sphorylation, neither compound had an effect on SAMC-induced apoptosis. These data confirm that SAMC can induce apoptosis in colon cancer cells primarily via JNK-dependent pathway in the first 24 h [5, 23]. Thirdly, SAMC can directly target mitochon-dria to initiate apoptosis in cancer cells. SAMC treatment (300 μmol·L−1) strongly induced the loss of mitochondrial mem-brane potential in SW480 cells, leading to the cytochrome crelease from inner membrane of mitochondria, to induce cellular apoptosis via the intrinsic apoptotic pathway [22].
    Liang et al. constructed a stable luciferase expression system of colon cancer cell line (SW620-Fluc) to establish a xenograft mice model, which was convenient in viewing the in vivo anti-tumor effect of SAMC via bioluminescence im-aging technique. They found that the fluorescence intensity of tumor in SAMC-treated group were significantly weaker than that in the untreated group at day 12 and 16 after cell implan-tation. Histopathological results revealed that SAMC directly triggers cell apoptosis within tumor by activated caspase 3 and cleaved PARP1 [24], without causing toxic symptoms in vital organs (e.g. heart and liver).