Traditional Chinese medicine, based on theories developed and practiced for >2,000 years, is one of the most common complementary and alternative types of medicine currently used in the treatment of patients with breast cancer. Ruanjian Sanjie (RJSJ) decoction, is composed of four herbs, including Ban xia (Pinellia ternata), Xia ku cao (Prunella vulgaris), Shan ci gu (Cremastra appendiculata) and Hai zao (Sargassum pallidum), and has traditionally been used for softening hard lumps and resolving hard tissue masses. However, the active compounds and mechanisms of action of RJSJ remain unknown. The present study demonstrated the antitumor activity of RJSJ against Ehrlich ascites carcinoma in Swiss albino mice and breast cancer xenografts in nude mice. Notably, RJSJ does not induce body weight loss, immune function toxicity or myelosuppression in mice, indicating that it is safe and well tolerated. In addition, RJSJ shows potent cytotoxicity against breast cancer cells in vitro by the suppression of the anti-apoptotic proteins B-cell lymphoma 2 and survivin, leading to the activation of caspase-3/7 and caspase-9, and the apoptotic cascade. These findings provide a clear rationale to explore the therapeutic strategy of using RJSJ alone or in combination with chemotherapeutic agents for breast cancer patients and the characterization of its active principles.
In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple‐negative breast cancer cell line MDA‐MB‐231. Cellular functional assays showed that representative compounds could induce G1‐phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl‐2, caspase‐3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3‐II and Beclin‐1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E‐BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA‐MB‐231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple‐negative breast cancers, possibly mesenchymal stem‐like subtype.
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