Co-delivery of the autophagy inhibitor si-Beclin1 and the doxorubicin nano-delivery system for advanced prostate cancer treatment

2021 ◽  
pp. 088532822110602
Author(s):  
Chuling Hu ◽  
Fenfen Gu ◽  
Chunai Gong ◽  
Qingming Xia ◽  
Yuan Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Treatment ◽  
Tumor Therapy ◽  
Pi3k Pathway ◽  
Tumor Resistance ◽  
Drug Induced ◽  
Inhibitory Potential ◽  
Induced Apoptosis ◽  
Micelle System

Resistance to apoptosis is a key mechanism underlying how cancer cells evade tumor therapy. Autophagy can prevent anticancer drug-induced apoptosis and promote tumor resistance. The purpose of this study was to improve the sensitivity and efficacy of chemotherapeutic drugs through the inhibition of autophagy. Hydrophobic doxorubicin–hydrazone–caproyl–maleimide (DOX-EMCH) and autophagy-inhibiting si-Beclin1 were simultaneously delivered via the amphiphilic peptide micelle system (Co-PMs) using poly(L-arginine)–poly(L-histidine)–DOX-EMCH as the copolymer building unit. The constructed micelle system promoted the escape of si-Beclin1 from endosomes and the release of DOX into the nucleus. The Co-PMs exhibited 2.7-fold higher cytotoxicity and proapoptotic ability in PC3 cells than DOX treatment alone, demonstrating that si-Beclin1 could inhibit the autophagic activity of prostate cancer (PCa) cells by targeting the type III PI3K pathway and enhance the sensitivity of the cells to the chemotherapeutic drug DOX. In addition, the peptide micelles successfully passively targeted DOX and si-Beclin1 to the tumor tissue. Compared with DOX or si-Beclin1 treatment alone, the Co-PMs showed a 3.4-fold greater tumor inhibitory potential in vivo, indicative of a significant antiproliferative effect. Our results suggested that the Co-PMs developed in this study have the potential to combine autophagy inhibition and chemotherapy in cancer treatment, especially for PCa.

scholarly journals Synergistic Effect of Autophagy Inhibitor Si-beclin1 Combined With the Doxorubicin Nano-delivery System Against Advanced Prostate Cancer

2020 ◽  
Author(s):  
Chuling Hu ◽  
Fenfen Gu ◽  
Yuan Gao ◽  
Chunai Gong ◽  
Qingming Xia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Therapy ◽  
Pi3k Pathway ◽  
Combination Method ◽  
Tumor Resistance ◽  
Proliferative Effect ◽  
Pc3 Cells ◽  
Autophagy Activity ◽  
Micelle System

Abstract Apoptosis tolerance is an important mechanism of tumor resistance in tumor therapy. Autophagy can prevent apoptosis induced by antitumor drugs and promote tumor resistance. The purpose of the presentn study was to improve the sensitivity of chemotherapeutic drugs and enhance the efficacy by inhibiting autophagy. In the present study, hydrophobic doxorubicin-hydrazone-caproyl-maleimide (DOX-EMCH) and autophagy-inhibitory si-Beclin1 were simultaneously delivered via the amphiphilic peptide micelle system(Co-MPs) using ploy(L-arginine)-poly(L-histidine)-DOX-EMCH as the copolymer building unit. It was found that the constructed micelle system promoted the escape of si-Beclin1 from endosomes and the release of DOX into the nucleus and the Co-MPs exhibited 2.7–fold higher cytotoxicity and apoptosis, in PC3 cells than DOX treatment alone did, which demonstrates the si-Beclin1 inhibited the autophagy activity of prostate cancer (PCa) cells by targeting the type III PI3K pathway and improve the sensitivity to the chemotherapy drug DOX. In addition, the peptide micelles successfully targeted DOX and si-Beclin1 passively to the tumor tissue. Compared with DOX or si-Beclin1 treatment alone, the Co-MPs showed a 3.4-fold greater tumor inhibition in vivo, which demonstrated a synergistic anti-proliferative effect in vivo. Our results suggest that the Co-MPs developed in this study may prove to be a promising combination method to provide autophagy inhibition and chemotherapy in cancer treatment, especially for PCa.

scholarly journals Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-wen Cheng ◽  
Li-xia Duan ◽  
Yang Yu ◽  
Pu Wang ◽  
Jia-le Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Cell Contact ◽  
Activity Levels ◽  
Tumor Resistance ◽  
Cell Cell

Abstract Background Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. Methods First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. Results We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Conclusions Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa.

Methylglyoxal–Induced Apoptosis in Human Prostate Carcinoma: Potential Modality for Prostate Cancer Treatment

2000 ◽  
Vol 37 (6) ◽  
pp. 728-734 ◽  
Author(s):  
Dan M. Milanesa ◽  
Muhammad S. Choudhury ◽  
Camille Mallouh ◽  
Hiroshi Tazaki ◽  
Sensuke Konno
Keyword(s):  
Prostate Cancer ◽  
Cancer Treatment ◽  
Prostate Carcinoma ◽  
Human Prostate ◽  
Prostate Cancer Treatment ◽  
Human Prostate Carcinoma ◽  
Induced Apoptosis

Human U3 protein 14a plays an anti-apoptotic role in cancer cells

2017 ◽  
Vol 398 (11) ◽  
pp. 1247-1257 ◽  
Author(s):  
Teng Ma ◽  
Chenxi Lu ◽  
Yafei Guo ◽  
Chunfeng Zhang ◽  
Xiaojuan Du
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Protein Level ◽  
Tumor Therapy ◽  
Caspase Inhibitor ◽  
Chemotherapeutic Drug ◽  
Intrinsic Pathway ◽  
Down Regulation ◽  
Drug Induced ◽  
Induced Apoptosis

AbstractHuman U three protein 14a (hUTP14a) binds p53 and promotes p53 degradation. Here, we report that hUTP14a plays an anti-apoptotic role in tumor cells through a p53-independent pathway. Knockdown of hUTP14a activated the intrinsic pathway of apoptosis and sensitized tumor cells to chemotherapeutic drug-induced apoptosis. In addition, the protein level of hUTP14a decreased upon chemotherapeutic drug- or irradiation-induced apoptosis. Importantly, the decrease of hUTP14a during induced apoptosis was not blocked by pan-caspase inhibitor z-VAD-FMK, indicating that the down-regulation of hUTP14a is an upstream event in apoptosis. Furthermore, ectopically expressed hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis. In summary, our data showed that hUTP14a protected tumor cells from chemotherapeutic drug-induced apoptosis and thus might possess a potential as a target for anti-tumor therapy.

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