Autophagy in cancer resistance to paclitaxel: Development of combination strategies

Škubník, Jan; Pavlíčková, Vladimíra Svobodová; Ruml, Tomáš; Rimpelová, Silvie

doi:10.1016/j.biopha.2023.114458

Cited by 22 publications

(9 citation statements)

References 112 publications

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“…Its mechanism of action is to cause mitochondrial damage in tumor cells to release ROS and further activate apoptotic pathways [ 23 , 24 ]. In fact, tumor cells can eliminate damaged mitochondria through the up-regulation of autophagy activity to reduce apoptotic factors and thereby avoid killing [ 25 , 26 ], resulting in drug resistance of tumor cells and reducing drug efficacy. Based on this resistance phenomenon, it appears that autophagy induced by cisplatin and paclitaxel is cytoprotective in nature.…”

Section: Resultsmentioning

confidence: 99%

Identification of Fangjihuangqi Decoction as a late-stage autophagy inhibitor with an adjuvant anti-tumor effect against non-small cell lung cancer

et al. 2023

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Background Clinically, although chemotherapy is one of the most commonly used methods of treating tumors, chemotherapeutic drugs can induce autophagic flux and increase tumor cell resistance, leading to drug tolerance. Therefore, theoretically, inhibiting autophagy may improve the efficacy of chemotherapy. The discovery of autophagy regulators and their potential application as adjuvant anti-cancer drugs is of substantial importance. In this study, we clarified that Fangjihuangqi Decoction (FJHQ, traditional Chinese medicine) is an autophagy inhibitor, which can synergistically enhance the effect of cisplatin and paclitaxel on non-small cell lung cancer (NSCLC) cells. Methods We observed the changes of autophagy level in NSCLC cells under the effect of FJHQ, and verified the level of the autophagy marker protein and cathepsin. Apoptosis was detected after the combination of FJHQ with cisplatin or paclitaxel, and NAC (ROS scavenger) was further used to verify the activation of ROS-MAPK pathway by FJHQ. Results We observed that FJHQ induced autophagosomes in NSCLC cells and increased the levels of P62 and LC3-II protein expression in a concentration- and time-gradient-dependent manner, indicating that autophagic flux was inhibited. Co-localization experiments further showed that while FJHQ did not inhibit autophagosome and lysosome fusion, it affected the maturation of cathepsin and thus inhibited the autophagic pathway. Finally, we found that the combination of FJHQ with cisplatin or paclitaxel increased the apoptosis rate of NSCLC cells, due to increased ROS accumulation and further activation of the ROS-MAPK pathway. This synergistic effect could be reversed by NAC. Conclusion Collectively, these results demonstrate that FJHQ is a novel late-stage autophagy inhibitor that can amplify the anti-tumor effect of cisplatin and paclitaxel against NSCLC cells.

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Section: Resultsmentioning

confidence: 99%

Identification of Fangjihuangqi Decoction as a late-stage autophagy inhibitor with an adjuvant anti-tumor effect against non-small cell lung cancer

et al. 2023

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“…The major mechanism of its activity is a capacity to disrupt microtubule-assembling dynamics and induce cell cycle arrest at the G2/M phase, leading to apoptosis. However, as for other chemotherapeutic drugs, a major problem of PTX application is the development of chemoresistance due to protective autophagy [88].…”

Section: Chloroquine and Paclitaxel (Ptx)mentioning

confidence: 99%

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

Agalakova

2024

IJMS

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Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required.

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“…However, the development of resistance to paclitaxel and its toxic side effects have limited its effectiveness when used alone (Abu et al, 2019;Smith et al, 2022;Hashemi et al, 2023). Currently, there is a lot of interest in combining paclitaxel with other drugs for cancer treatment (Yu et al, 2020;Xu et al, 2021;Škubník et al, 2023). This combination therapy approach not only helps to reduce the toxic side effects of chemotherapy but also allows for the reduction of the dosage of traditional chemotherapy drugs.…”

Section: Introductionmentioning

confidence: 99%

Benserazide, a cystathionine beta-synthase (CBS) inhibitor, potentially enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and the HIF1-α/VEGF pathway

Zhao,

Feng,

Wang

et al. 2024

Front. Pharmacol.

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Cancer targeted therapy is essential to minimize damage to normal cells and improve treatment outcomes. The elevated activity of Cystathionine beta-synthase (CBS), an enzyme responsible for producing endogenous hydrogen sulfide (H2S), plays a significant role in promoting tumor growth, invasiveness, and metastatic potential. Consequently, the selective inhibition of CBS could represent a promising therapeutic strategy for cancer. Currently, there is much interest in combining paclitaxel with other drugs for cancer treatment. This study aimed to investigate the efficacy of combining benserazide, a CBS inhibitor, with paclitaxel in treating tumors. Firstly, we demonstrated CBS is indeed involved in the progression of multiple cancers. Then it was observed that the total binding free energy between the protein and the small molecule is −98.241 kJ/mol. The release of H2S in the group treated with 100 μM benserazide was reduced by approximately 90% compared to the negative control, and the thermal denaturation curve of the complex protein shifted to the right, suggesting that benserazide binds to and blocks the CBS protein. Next, it was found that compared to paclitaxel monotherapy, the combination of benserazide with paclitaxel demonstrated stronger antitumor activity in KYSE450, A549, and HCT8 cells, accompanied by reduced cell viability, cell migration and invasion, as well as diminished angiogenic and lymphangiogenic capabilities. In vivo studies showed that the combined administration of benserazide and paclitaxel significantly reduced the volume and weight of axillary lymph nodes in comparison to the control group and single administration group. Further mechanistic studies revealed that the combination of benserazide and paclitaxel significantly suppressed the S-sulfhydration of SIRT1 protein, thereby inhibiting the expression of SIRT1 protein and activating SIRT1 downstream Notch1/Hes1 signaling pathway in KYSE450, A549, and HCT8 cells. Meanwhile, we observed that benserazide combined with paclitaxel induced a more significant downregulation of HIF-1α, VEGF-A, VEGF-C, and VEGF-D proteins expression levels in KYSE450, A549, and HCT8 cells compared to paclitaxel alone. These findings indicated that benserazide enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and down-regulating HIF-1α/VEGF signaling pathway. This study suggests that benserazide may have potential as a chemosensitizer in cancer treatment.

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Autophagy in cancer resistance to paclitaxel: Development of combination strategies

Cited by 22 publications

References 112 publications

Identification of Fangjihuangqi Decoction as a late-stage autophagy inhibitor with an adjuvant anti-tumor effect against non-small cell lung cancer

Identification of Fangjihuangqi Decoction as a late-stage autophagy inhibitor with an adjuvant anti-tumor effect against non-small cell lung cancer

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

Benserazide, a cystathionine beta-synthase (CBS) inhibitor, potentially enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and the HIF1-α/VEGF pathway

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