Cepharanthine Hydrochloride Improves Cisplatin Chemotherapy and Enhances Immunity by Regulating Intestinal Microbes in Mice

Abstract

Chemotherapy is one of the major treatment strategies for esophageal squamous cell carcinoma (ESCC). Unfortunately, most chemotherapeutic drugs have significant impacts on the intestinal microbes, resulting in side effects and reduced efficiency. Therefore, new strategies capable of overcoming these disadvantages of current chemotherapies are in urgent need. The natural product, Cepharanthine hydrochloride (CEH), is known for its anticancer and immunoregulatory properties. By sequencing the V4 region of 16S rDNA, we characterized the microbes of tumor-bearing mice treated with different chemotherapy strategies, including with CEH. We found that CEH improved the therapeutic effect of CDDP by manipulating the gut microbiota. Through metagenomic analyses of the microbes community, we identified a severe compositional and functional imbalance in the gut microbes community after CDDP treatment. However, CEH improved the effect of chemotherapy and ameliorated CDDP treatment-induced imbalance in the intestinal microbes. Mechanically, CEH activated TLR4 and MYD88 innate immune signaling, which is advantageous for the activation of the host's innate immunity to exert a balanced intestinal environment as well as to trigger a better chemotherapeutic response to esophageal cancer. In addition, TNFR death receptors were activated to induce apoptosis. In summary, our findings suggest that chemotherapy of CDDP combined with CEH increased the effect of chemotherapy and reduced the side effects on the microbes and intestinal mucosal immunity. We believe that these findings provide a theoretical basis for new clinical treatment strategies.

Administration of Lactobacillus reuteri Combined with Clostridium butyricum Attenuates Cisplatin-Induced Renal Damage by Gut Microbiota Reconstitution, Increasing Butyric Acid Production, and Suppressing Renal Inflammation

“…This was associated with a significant decrease in circulating LPS, and showed a significant alleviation of renal damage [ 51 ]. Butyrate can not only inhibit pathogenic bacteria while stimulating the growth of beneficial bacteria [ 69 ], but can also decrease the levels of microbiota-dependent components, such as endotoxin [ 49 ]. Another reason for LCs ameliorated cisplatin nephrotoxicity was probably because of a decrease in the number of indole-producing bacteria and maintenance of intestinal barrier function caused by the decreased levels of the IS [ 56 ] and endotoxin [ 41 ] or the elevation in the amount of Bifidobacterium [ 62 , 63 ].…”

Potent antitumor activity of cepharanthine against triple‑negative breast cancer spheroids compared with tetrandrine

“…This suggests that higher concentrations of CEP are required to have an effect on cancer spheroids. Furthermore, a previous study reported that a conventional anticancer medicine, cisplatin, in combination with CEP increased the efficacy of the conventional drug in esophageal squamous cell carcinoma and decreased its side effects on gut microorganisms and intestinal mucosal immunity ( 46 ). Detailed analysis of the effect of CEP combined with cisplatin against breast cancer cells is warranted in future studies.…”

Rps15a Imparts Chemoresistance by Regulating Cd44 Expression and Cell Stemness in Esophageal Squamous Cell Carcinoma

“…SDS-PAGE was used to separate the proteins, which were then transferred onto PVDF membranes (Millipore, MA, USA) as previously described. [17] The membranes were treated overnight at 4℃ with primary antibodies, washed and incubated with secondary antibodies for 2 hours at 25℃. The uorescence intensity of target proteins was detected using an Enhanced Chemiluminescence Anti-RPS15A antibody (AP4804a) was purchased from ABGENT, USA.…”