Abstract
Simple SummaryWe found a novel cyclic pentadepsipeptide, N-methylsansalvamide (MSSV), and evaluated its anti-tumor action against bladder cancer using in vitro and in vivo model systems. Additionally, we report its anti-angiogenic responses both in vitro and in vivo. Moreover, acute toxicity test and tissue staining for liver function revealed that orally administered MSSV (2000 mg/kg for 14 days) exerted no harmful effects as it did not cause animal death, undesirable weigh alteration, adverse clinical symptoms, and abnormal biochemical marker levels (AST, ALT).Here, we explored the anti-tumor efficacy of a cyclic pentadepsipeptide, N-methylsansalvamide (MSSV), in bladder cancer. MSSV inhibited the proliferation of both bladder cancer 5637 and T24 cells, which was attributed to the G1-phase cell cycle arrest, apoptosis induction, and alteration of mitogen-activated protein kinases (MAPKs) and protein kinase b (AKT) signaling pathways. Additionally, the treatment of bladder cancer cells with MSSV suppressed migratory and invasive potential via the transcription factor-mediated expression of matrix metalloproteinase 9 (MMP-9). MSSV abrogated vascular endothelial growth factor (VEGF)-induced angiogenic responses in vitro and in vivo. Furthermore, our result showed the potent anti-tumor efficacy of MSSV in a xenograft mouse model implanted with bladder cancer 5637 cells. Finally, acute toxicity test data obtained from blood biochemical test and liver staining indicated that the oral administration of MSSV at 2000 mg/kg caused no adverse cytotoxic effects. Our preclinical data described the potent anti-angiogenic and anti-tumor efficacy of MSSV and showed no signs of acute toxicity, thereby suggesting the putative potential of oral MSSV as a novel anti-tumor agent in bladder cancer treatment.
Highlights
Bladder cancer is considered a critical malignancy worldwide
Polyclonal antibodies specific to extracellular signal regulated kinase (ERK), phosphoERK, p38MAPK, phospho-p38MAPK, c-Jun N-terminal kinase (JNK), phospho-JNK, AKT, and phospho-AKT were obtained from Cell Signaling (Danvers, MA, USA)
Polyclonal antibodies specific to FAS, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), X-linked inhibitor of apoptosis protein (XIAP), poly(ADP-ribose) polymerase-1 (PARP-1), caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and Cell Signaling (Danvers, MA, USA)
Summary
Bladder cancer is considered a critical malignancy worldwide. Approximately, 90% of the bladder cancers manifest as transitional cell carcinoma (TCC), which are categorized as non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) [1,2,3]. The main process in the development and progression of bladder cancer is strongly associated with proliferation and metastasis of tumor cells [3]. N-methylsansalvamide, which was purified from green algae in ocean, had a molecular structure comprising one hydroxy acid (leucic acid (O-Leu)) and four amino acids (phenylalanine (Phe), leucine (Leu), N-methyl-leucine (NMeLeu), and valine (Val)) [11,13]. Both sansalvamide A and N-methylsansalvamide have reported a weak anticancer effect [11,12,13]. To our knowledge, the anti-tumor efficacy, anti-angiogenic effect, and single-dose acute toxicity of MSSV in cancer cells both in vitro and in vivo are reported for the first time
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