Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

Ashrafizadeh, Milad; Paskeh, Mahshid Deldar Abad; Mirzaei, Sepideh; Gholami, Mohammad Hossein; Zarrabi, Ali; Hashemi, Farid; Hushmandi, Kiavash; Hashemi, Mehrdad; Nabavi, Noushin; Crea, Francesco; Ren, Jun; Klionsky, Daniel J.; Kumar, Alan Prem; Wang, Yuzhuo

doi:10.1186/s13046-022-02293-6

Table 4 Targeting autophagy by anti-cancer compounds in prostate cancer therapy

From: Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

Anti-tumor compound	Study design	Effect on autophagy	Signaling network	Remarks	Refs
Abiraterone	LNCaP, DU145 and PC3 cells 6, 10 and 16 μM	Induction	ATG5 LC3-II SQSTM1	Enhancing levels of ATG5 and LC3-II. Downregulated SQSTM1. Triggering both autophagy and apoptosis. Inhibition of adaptive autophagy promotes potential of abiraterone in apoptosis induction in prostate cancer cells.	[364]
Icariside II	DU145 cells 0–90 μM	Induction	PI3K-AKT-MTOR	Decreasing proliferation and viability of cancer cells in a time- and dose-dependent manner. Apoptosis and cell cycle arrest induction. Inducing autophagy through PI3K-AKT-MTOR inhibition. Upregulating BECN1 and LC3-II.	[365]
Huaier	PC3 cells 0–8 mg/ml	Induction	ATG3 ATG5 BECN1 LC3-II	Autophagy induction. Decreasing viability and proliferation of cancer cells. Impairing cancer migration. Upregulation of ATG3, ATG5, BECN1 and LC3-II.	[366]
Sunitinib	PC3 and LNCaP cells 5, 10 and 20 μM	Induction	MAPK1/ERK2-MAPK3/ERK1 MTOR	Inhibiting MTOR phosphorylation. Triggering MAPK1-MAPK3 phosphorylation. Autophagy inhibition enhances anti-tumor activity of sunitinib in prostate cancer therapy.	[367]
Apalutamide	LNCaP cells 0–100 μM	Induction	ATG5 BECN1 LC3	Overexpression of ATG5, BECN1 and LC3 to stimulate autophagy. Using autophagy inhibitor enhances efficacy of apalutamide in apoptosis induction in prostate cancer cells.	[365]
NCL1 (histone lysine demethylase 1 inhibitor)	PC3 and 22Rv1 cells PCai1 subcutaneous tumor model 0–100 mM	Induction	–	Triggering both apoptosis and autophagy in prostate cancer cells. Inhibiting autophagy potentiates anti-tumor activity of NCL1, showing anti-tumor activity.	[368]
Reverse transcriptase inhibitors, efavirenz and SPV122.2	PC3 and LNCaP cells 20 μM	Induction	–	Autophagy induction participates in anti-proliferative activity of these agents	[369]
Everolimus Propachlor	PC3 cells 6.15 (propachlor) and 0.70 μM (everolimus)	Induction	BECN1 ATG512–ATG5 complex	Promoting expression level of BECN1. Upregulation of ATG12–ATG5 conjugate. Inducing autophagic cell death. Sensitizing prostate cancer cells to apoptosis.	[370]
Monascuspilion	PC3 cells 0–45 μM	Induction	AKT-MTOR	Suppressing AKT-MTOR axis and subsequent induction of autophagy. Decreasing viability and survival of prostate cancer cells.	[371]
Atorvastatin	PC3 cells and LNCaP cells 5 μM	Induction	BCL2 MIR182 CDKN1A/p21	BCL2 downregulation, and MIR182 and CDKN1A upregulation. Exerting anti-proliferation activity. Autophagy induction.	[372]
Lithocholic acid	PC3 and DU-145 cells 5–75 μM	Induction	ATG5	Reducing survival of prostate cancer cells. Autophagy induction via ATG5 upregulation.	[373]
Peperomin E	DU145 cells	Induction	AKT-MTOR	Stimulating both apoptosis and autophagy. Targeting the AKT-MTOR axis. Autophagy plays a protective role. Autophagy inhibition may promote anti-tumor activity of peperomin E against prostate cancer cells.	[374]
Oridonin	PC3 and LNCaP cell lines 0–100 μmol/L	Induction	–	Enhancing conversion of LC3-I to LC3-II. Increasing autophagosome formation. Autophagy induction. CDKN1A upregulation and subsequent apoptosis in prostate cancer cells. Autophagy inhibition reverses CDKN1A upregulation.	[375]
Phenethyl isothiocyanate	PC-3 and LNCaP cells 5 μM	Induction	–	The significant decrease occurs in progression of prostate cancer cells exposed to PEITC The increased levels and generation of ROS by PEITC are responsible for triggering autophagy in prostate cancer cells	[376]
Lu01-M (a secondary metabolite)	PC3, DU145, and LNCaP cells 1.56, 3.125 and 6.25 μg/mL	Induction	–	The Lu01-M triggered DNA damage, apoptosis, necrosis and autophagy in prostate cancer cells, but autophagy function was pro-survival, and its inhibition should be considered in next studies	[374]
Plectranthoic acid	DU145, CW22Rν1, PC3, NB26, and A375 cells 20–40 μM	Induction	MTOR	Plectranthoic acid inhibits phosphorylation of mTOR signaling to induce autophagy and along with apoptosis are responsible for reducing survival of prostate cancer cells	[377]
Curcumin	22rv1, LNCaP, DU145 and PC-3 cells 10, 20, 50, 75, 100 μM	Induction	WNT	Inhibiting Wnt signaling and preventing interaction of β-catenin and TCF-4 protein in triggering autophagy and reducing prostate cancer progression	[378]
Zoledronic acid	PC-3, DU-145, LNCaP and CRW22Rv1 cell lines 100 μM	Induction	–	Inducing autophagy and apoptosis decrease prostate cancer progression, and using autophagy and apoptosis inhibits promotes proliferation and viability of tumor cells	[379]
Cysmethynil	PC-3 cells 0–50 μM	Induction	MTOR	Mediating cell death and G1 phase arrest Triggering autophagic cell death	[380]
Marchantin M	PC-3 cells 2.5, 5, 10 and 20 μM	Induction	PI3K-AKT-MTOR EIF2AK3/PERK-EIF2A	Triggering autophagic cell death in prostate tumor cells via suppressing PI3K-AKT-MTOR axis and inducing PRK/elF2α axis	[381]
Glycyrrhiza glabra	PC3 cells 0–100 nM	Induction	LC3A ULK1 AMBRA1	Triggering autophagy via enhancing expression levels of LC3A, ULK1 and AMBRA1. Anti-tumor activity of autophagy. Apoptosis induction.	[382]
Fenofibrate	DU145 and PC3 cells	Induction	AMPK	AMPK phosphorylation and subsequent induction of autophagy. Increased sensitivity of prostate cancer cells to docetaxel chemotherapy.	[383]
Gossypetin	PCa, LNCaP and DU145 cell lines 0–100 μM	Induction	ATG5	ATG5 upregulation and subsequent triggering of autophagy. Reducing tumor growth in vivo.	[384]
Docetaxel	PC3 and LNCaP cell lines 1, 10 and 100 nM	Inhibition	PI3K-AKT-MTOR	Inhibiting PI3K expression. Autophagy suppression. Enhancing apoptosis in cancer cells.	[385]
Hydroxytyrosol	PC3 cells	Inhibition	–	Increasing ROS levels in autophagy impairment to diminish proliferation and viability of prostate cancer cells.	[386]
Cytolethal distending toxin	LAPC4 PCa cells 0–500 nM	Inhibition	MYC HMGB1	Preventing radiation-mediated autophagy via downregulating MYC expression. Further inhibition of autophagy by HMGB1 inhibition.	[387]
Rapamycin	PC3, DU145 and LNCaP cells	Inhibition	BECN1	Enhancing potential of radiotherapy in prostate cancer suppression. Decreased expression level of BECN1. Providing radio-sensitivity via autophagy inhibition.	[388]
Propranolol	H33258 cells 100 μM	Inhibition	–	Suppressing prostate cancer progression. Enhancing autophagosome accumulation due to autophagy blockade. Promoting potential of 2-deoxyglucose in glycolysis inhibition and preventing prostate cancer progression. Autophagy inhibition exacerbates ER stress.	[389]
Pyroglutamate-modified peptide (pE-K092D)	MDA-Pca-2b cell line	Inhibition	–	Proliferation inhibition, cytoskeleton disruption and autophagy inhibition are responsible for decreased progression of prostate cancer cells	[390]

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