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.
SiegelRLMillerKDJemalA. Cancer statstics, 2019. CA Cancer J Clin2019; 69(1): 7–34.
2.
NaderRAmmJEAragon-ChingJB. Role of chemotherapy in prostate cancer. Asian J Androl2018; 20(3): 221–229.
3.
BlessingAMRajapaksheKBolluLR, et al.Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression. Autophagy2017; 13(3): 506–521.
4.
CaiZChenWZhangJ, et al.Androgen receptor: what we know and what we expect in castration-resistant prostate cancer. Int Urol Nephrol2018; 50(10): 1753–1764.
5.
NevedomskayaEBaumgartSJHaendlerB. Recent advances in prostate cancer treatment and drug discovery. Int J Mol Sci2018; 19(5): 1359.
6.
QuinnDISandlerHMHorvathLG, et al.The evolution of chemotherapy for the treatment of prostate cancer. Ann Oncol2017; 28(11): 2658–2669.
EvansAJ. Treatment effects in prostate cancer. Mod Pathol2018; 31(S1): S110–S121.
9.
Ramos-EsquivelAFernándezCZeledónZ. Androgen-deprivation therapy plus chemotherapy in metastatic hormone-sensitive prostate cancer. A systematic review and meta-analysis of randomized clinical trials. Urol Oncol2016; 34(8): 335.e9–335.e19.
10.
GuptaSGuptaPKDharanivasanG, et al.Current prospects and challenges of nanomedicine delivery in prostate cancer therapy. Nanomedicine (Lond)2017; 12(23): 2675–2692.
11.
FarrowJMYangJCEvansCP. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol2014; 11(9): 508–516.
12.
NaponelliVModernelliABettuzziS, et al.Roles of autophagy induced by natural compounds in prostate cancer. Biomed Res Int2015; 2015: 121826.
13.
LiYJLeiYHYaoN, et al.Autophagy and multidrug resistance in cancer. Chin J Cancer2017; 36(1): 52.
14.
ChenCLuLYanS, et al.Autophagy and doxorubicin resistance in cancer. Anticancer Drugs2018; 29(1): 1–9.
15.
WirawanEBergheTVLippensS, et al.Autophagy: for better or for worse. Cell Res2012; 22(1): 43–61.
16.
YunCWLeeSH. The roles of autophagy in cancer. Int J Mol Sci2018; 19(11): 3466.
17.
OnoratiAVDyczynskiMOjhaR, et al.Targeting autophagy in cancer. Cancer2018; 124(16): 3307–3318.
18.
HsiehMJLinCWYangSF, et al.A combination of pterostilbene with autophagy inhibitors exerts efficient apoptotic characteristics in both chemosensitive and chemoresistant lung cancer cells. Toxicol Sci2014; 137(1): 65–75.
19.
PanBChenDHuangJ, et al.HMGB1-mediated autophagy promotes docetaxel resistance in human lung adenocarcinoma. Mol Cancer2014; 13: 165.
20.
JiangYYangNZhangH, et al.Enhanced in vivo antitumor efficacy of dual-functional peptide-modified docetaxel nanoparticles through tumor targeting and Hsp90 inhibition. J Control Release2016; 221: 26–36.
21.
RohatgiRAJanusisJLeonardD, et al.Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene2015; 34(42): 5352–5362.
22.
LiangXHJacksonSSeamanM, et al.Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature1999; 402(6762): 672–676.
23.
RussoMRussoGL. Autophagy inducers in cancer. Biochem Pharmacol2018; 153: 51–61.
24.
DeSDasSSenguptaS. Involvement of HuR in the serum starvation induced autophagy through regulation of Beclin1 in breast cancer cell-line, MCF-7. Cell Signal2019; 61: 78–85.
25.
YangMYangXMYinDH, et al.Beclin1 enhances cisplatin-induced apoptosis via Bcl-2-modulated autophagy in laryngeal carcinoma cells Hep-2. Neoplasma. 2018; 65(1):42–48.
26.
AitaVMLiangXHMurtyV, et al.Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics1999; 59(1): 59–65.
27.
XiGHuXWuB, et al.Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells. Cancer Let2011; 307(2): 141–148.
28.
SaleemADvorzhinskiDSantanamU, et al.Effect of dual inhibition of apoptosis and autophagy in prostate cancer. Prostate2012; 72(12): 1374–1381.
29.
XiongXBFalamarzianAGargSM, et al.Engineering of amphiphilic block copolymers for polymeric micellar drug and gene delivery. J Control Release2011; 155(2): 248–261.
30.
GaucherGDufresneMHSantVP, et al.Block copolymer micelles: preparation, characterization and application in drug delivery. J Control Release2005; 109(1–3): 169–188.
31.
MaedaHNakamuraHFangJ. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev2013; 65(1): 71–79.
32.
MaruyamaK. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects. Adv Drug Deliv Rev2011; 63(3): 161–169.
33.
SmithSASelbyLIJohnstonAPR, et al.The endosomal escape of nanoparticles: toward more efficient cellular delivery. Bioconjug Chem2019; 30(2): 263–272.
34.
FutakiSSuzukiTOhashiW, et al.Arginine-rich peptides An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem2001; 276(8): 5836–5840.
35.
FutakiS. Membrane-permeable arginine-rich peptides and the translocation mechanisms. Adv Drug Deliver Rev2005; 57(4): 547–558.
36.
LorentsASäälikPLangelÜ, et al.Arginine-rich cell-penetrating peptides require nucleolin and cholesterol-poor subdomains for translocation across membranes. Bioconjug Chem2018; 29(4): 1168–1177.
37.
LächeltUKosPMicklerFM, et al.Fine-tuning of proton sponges by precise diaminoethanes and histidines in pDNA polyplexes. Nanomedicine2014; 10(1): 35–44.
38.
MidouxPPichonCYaouancJJ, et al.Chemical vectors for gene delivery: a current review on polymers, peptides and lipids containing histidine or imidazole as nucleic acids carriers. Br J Pharmacol2009; 157(2): 166–178.
39.
YinJRenWYangG, et al.L-Cysteine metabolism and its nutritional implications. Mol Nutr Food Res2016; 60(1): 134–146.
40.
TianMGuoFSunY, et al.A fluorescent probe for intracellular cysteine overcoming the interference by glutathione. Mol Nutr Food Res2016; 60(1): 134–146.
41.
TaiZGWangXYTianJ, et al.Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. Biomacromolecules2015; 16(4): 1119–1130.
42.
AcharyaSSahooSK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev2011; 63(3): 170–183.
43.
ConnerSDSchmidSL. Regulated portals of entry into the cell. Nature2003; 422(6927): 37–44.
44.
DerakhshankhahHJafariS. Cell penetrating peptides: a concise review with emphasis on biomedical applications. Biomed Pharmacother2018; 108: 1090–1096.
45.
Jafarzadeh-HolaghSHashemi-NajafabadiSShakiH, et al.Self-assembled and pH-sensitive mixed micelles as an intracellular doxorubicin delivery system. J Colloid Interf Sci2018; 1(523): 179–190.
46.
DuCLiangYMaQ, et al.Intracellular tracking of drug release from pH-sensitive polymeric nanoparticles via FRET for synergistic chemo-photodynamic therapy. J Nanobiotechnology2019; 717(1): 113.
47.
LiZQiuLChenQ, et al.pH-sensitive nanoparticles of poly(L-histidine)-poly(lactide-co-glycolide)-tocopheryl polyethylene glycol succinate for anti-tumor drug delivery. Acta Biomater2015; 11: 137–150.
48.
YameenBChoiWIVilosC, et al.Insight into nanoparticle cellular uptake and intracellular targeting. J Control Release2014; 190: 485–499.
49.
RossN LMunsellEVSabanayagamC, et al.Histone-targeted polyplexes avoid endosomal escape and enter the nucleus during postmitotic redistribution of ER membranes. Mol Ther Nucleic Acids2015; 4(2): e226.
50.
ZhouCZhongWZhouJ, et al.Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells. Autophagy2012; 8(8): 1215–1226.
51.
YoshiiSRMizushimaN. Monitoring and measuring autophagy. Int J Mol Sci2017; 18(9): 1865.
52.
FengQYuMZWangJC, et al.Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core–shell nanoparticles. Biomaterials2014; 35(18): 5028–5038.
53.
GomariHForouzandeh MoghadamMSoleimaniM, et al.Targeted delivery of doxorubicin to HER2 positive tumor models. Int J Nanomedicine2019; 14: 5679–5690.
54.
QianFStoweNLiuEH, et al.Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers. J Control Release2003; 91(1–2): 157–166.
55.
MaedaH. Polymer therapeutics and the EPR effect. J Drug Target2017; 25(9–10): 781–785.
56.
LvSXTangZHLiZQ, et al.Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials2014; 35(23): 6118–6129.
57.
LiXRYangXCLinZQ, et al.A folate modified pH sensitive targeted polymeric micelle alleviated systemic toxicity of doxorubicin (DOX) in multi-drug resistant tumor bearing mice. Eur J Pharm Sci2015; 76: 95–101.
58.
ZhangXDYangYLiangX, et al.Enhancing therapeutic effects of docetaxel-loaded dendritic copolymer nanoparticles by Co-Treatment with autophagy inhibitor on breast cancer. Theranostics2014; 4(11): 1085–1095.
