Abstract
Increasing evidence highlights the cardinal role of gut microbiota in tumorigenesis and chemotherapy outcomes. Paclitaxel (PTX), although as a first-line chemotherapy reagent for breast cancer, still requires for improvement on its efficacy and safety due to drug resistance and adverse effects. The present work explored the enhancement of a polysaccharide derived from spore of Ganoderma lucidum (SGP) with PTX in a murine 4T1-breast cancer model. Results showed that the combination of PTX and SGP displayed an improved tumor control, in which mRNA expression of several Warburg effect-related proteins, i.e., glucose transporter 3 (Glut3), lactate dehydrogenase A (Ldha), and pyruvate dehydrogenase kinase (Pdk), and the metabolite profile of tumor was evidently altered. Flowcytometry analysis revealed that the combination treatment recovered the exhausted tumor infiltration lymphocytes (TILs) via inhibiting the expressions of immune checkpoints (PD-1 and Tim-3), while PTX alone evidently increased that of CTLA-4. 16S rRNA sequencing revealed a restoration by the combination treatment on gut microbiota dysbiosis induced by PTX, especially that Bacteroides, Ruminococcus, and other 5 genera were significantly enriched while the cancer-risk genera, Desulfovibrio and Odoribacter, were decreased. Moreover, spearman correlation analysis showed that abundance of Ruminococcus was significantly negative-associated with the amount of frucotose-6-phosphate within the tumor. Collectively, the present study suggests the clinical implication of SGP as an adjuvant candidate for PTX against breast cancer, which possibly relies on the regulation of tumor metabolism and gut microbiota.
Highlights
Breast cancer, as one of the most threatening carcinoma, has taken the first place of cancer-related deaths in women population worldwide (Li et al, 2016; DeSantis et al, 2017)
Drug resistance and adverse effects call for elevation on its efficacy and safety (Gupta et al, 2014; Starobova and Vetter, 2017)
It was previously demonstrated that SGP alone is able to potentiate the Tc-based tumor immune surveillance with a benefit reshaping on gut microbiota (Su et al, 2018)
Summary
As one of the most threatening carcinoma, has taken the first place of cancer-related deaths in women population worldwide (Li et al, 2016; DeSantis et al, 2017). With the advances of experimental and clinical researches, strategies against breast cancer mainly include surgical resection, adjuvant chemotherapy, radiotherapy, and hormone therapy (PDQ Adult Treatment Editorial Board). Their efficacies remain unsatisfactory, due to the increasing drug resistance and adverse effects, and because there are limitations in the application of certain strategies, especially that triple-negative breast cancer does not respond hormonal or trastuzumab-based therapies (Reddy, 2011). Chemotherapies, mainly employing paclitaxel (PTX), are still the most common and costeffective treatments for breast cancer control. Continued hard work is required for update of the current regimens, and even a revolution, to improve the efficacy eliminating the adverse effects
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