Nanomaterial-Induced Autophagy - American Chemical Society

Review pubs.acs.org/molecularpharmaceutics

Nanomaterial-Induced Autophagy: A New Reversal MDR Tool in Cancer Therapy? Elisa Panzarini and Luciana Dini* Department of Biological and Environmental Science and Technology (Di.S.Te.B.A.), University of Salento, 73100 Lecce, Italy ABSTRACT: Most of the therapeutic strategies to counteract cancer imply killing of malignant cells. The most exploited cell death mechanism in cancer therapies is apoptosis, but recently, a lot of papers report that other mechanisms, mainly autophagy, could represent a new line of attack in the fight against cancer. One of the limitations for the effectiveness of the approved clinical treatments is the phenomenon of multidrug resistance (MDR) which enables the cancer cells to develop resistance to therapy, especially for chemotherapy. The MDR mechanisms include (a) decreased uptake of drug, (b) reduced intracellular drug concentration by efflux pumps, (c) altered cell cycle checkpoints, (d) altered drug targets, (e) increased metabolism of drugs, (f) induced emergency response genes to impair apoptotic pathway, and (g) altered drug detoxification. Great efforts have been made to reverse MDR. Currently, autophagy and nanosized drug delivery systems (DDSs) belonging to nanomaterials (NMs) provide alternative strategies to circumvent MDR. Nanosized DDSs are very promising tools to accumulate chemotherapeutics at targeting sites and control temporal and spatial drug release into tumor cells. On the other hand, autophagy could overrule drug resistance upon its activation by ensuring cell death via switching its prosurvival role to a prodeath one or by mediating the occurrence of cell death, i.e., apoptosis or necrosis. Likewise, the autophagy inhibition could counteract MDR by sensitizing the cells to anticancer molecules, i.e., Src family tyrosine kinase (SFK) inhibitors or 5-fluorouracil. Noteworthy, autophagy has been recently indicated to be a common cellular response to NMs, corroborating the fascinating idea of the exploitation of NMinduced autophagy in nanomedicine therapy. This review focuses on recently published literature about the relationship between MDR reversal and NMs or autophagy pointing to hypothesize a pivotal role of autophagy modulation induced by NMs in counteracting MDR. KEYWORDS: autophagy, nanosized drug delivery systems (DDSs), nanomaterials (NMs), cancer therapies, multidrug resistance (MDR)

1. INTRODUCTION

drug targets, increased metabolism of drug, induced emergency response genes to impair apoptotic pathway, and altered drug detoxification.7 These mechanisms depend on several factors acting in MDR occurrence: (i) the ATP-binding cassette (ABC) transporters,8 MDR protein P-glycoprotein (Pgp),9,10 MDR-associated proteins (MRPs)8,11−13 and breast cancer resistant protein (BCRP) that expels the drug molecules out of the cells; (ii) the lung resistance-related protein (LRP) that transports drugs away from their intracellular targets, sequestrates the drugs,13,14 and alters intracellular drug distribution;15,16 (iii) the phase II detoxification enzymes glutathione-S-transferases (GSTs) that chelate the platinum

Actually, chemotherapy, alone or in combination with other traditional or specialized approaches, is the most important and exploited strategy to fight cancer, one of the most devastating diseases in human health.1−3 At least 50 different types of chemotherapy drugs are currently available to efficiently kill tumor cells and treat about 200 different types of cancers. However, chemotherapy outcome is strictly hampered by a defense mechanism that ill cells display to defend themselves from toxic compounds. This process, called multidrug resistance (MDR), first described in the late 1970s,4 depends on the patient and the type of tumor, and occurs when drugs are used for an extended period or sometimes even after use for a short time,5,6 contributing to therapeutic failure and tumor relapses in 90% of oncologic patients.7 MDR is the result of numerous mechanisms, such as decreased uptake of drug, reduced intracellular drug concentration by efflux pumps, altered cell cycle checkpoints, altered © XXXX American Chemical Society

Special Issue: Drug Delivery and Reversal of MDR Received: January 21, 2014 Revised: June 9, 2014 Accepted: June 12, 2014

A

dx.doi.org/10.1021/mp500066v | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

Review

represent safe and innovative tools to treat and diagnose cancer since they are capable to bypass crucial biological barriers and to deliver multiple agents directly to cancer cells and tumor microenvironment adjacent tissues.41 NMs efficiently target tumor cells by exploiting several features of tumor, such as leaky and defective tumor vasculature and poor lymphatic drainage resulting in an enhanced permeability and retention.42 The main nanoconstructs exploited in molecules delivery are liposomes,43 micelles,44 niosomes,45 nanoparticles (NPs),41 dendrimers46 and nanofibers.47 In the context of cancer therapy, nanocarriers can carry a complex and highly concentrated therapeutic “payload”, can improve drug affinity and specificity for target cells by attaching to multivalent targeting ligands, and can simultaneously and/or serially release multiple drug molecules allowing combinatorial cancer therapy.48 A list of the most recent proposed cancer chemicals vehicled by NMs is reported in Panzarini et al.37 In addition, NMs can synergize with chemotherapy and with new nonconventional cancer therapies, such as photodynamic therapy (PDT),49,50 internal radiotherapy,51,52 and gene therapy.53,54 In particular, combination cancer chemotherapy, i.e., simultaneous use of two or more drugs to treat a tumor, and use of NMs to deliver the drugs are two areas showing significant promise in cancer treatment. In fact, contemporary use of two or more drugs enables synergism among different drugs against different cancer promoting pathways as well as the precise drug delivery ensured by NMs enhanced therapeutic effectiveness and side effects reduction by optimizing drugs pharmacokinetic. Among drug-containing NMs, liposomes, polymeric and silica NPs, and dendrimers that ensure vehicle uniformity, ratiometric drug loading and temporal drug release are very important. In addition to traditional anticancer drugs, they are able to codeliver a new emerging classes of oncological therapeutics, small interfering RNA (siRNA), and antiangiogenic agents.55 Liposomes, amphiphilic lipid molecules assembled into bilayered spherical vesicles stabilized by cholesterol incorporation,56 are the most established and highly versatile drug vehicles. Their structure allows the simultaneous loading of hydrophilic and hydrophobic drugs57,58 and the control of the drugs’ molar ratio as it dictates the synergic, additive, or antagonist action of the drugs.30,59−62 In clinical trials several products are currently used: CPX351, a liposomal formulation loaded with cytarabine and daunorubicin in a 5:1 ratio, and CPX-1, 1:1 irinotecan and floxouridine liposome, are under phase II clinical trial for the treatment of acute myeloid leukemia63 and colorectal cancer64 respectively. A pivotal study of Tardi and co-workers65 suggests the high efficacy of a new liposomal formulation, CPX-571 (7:1 molar ratio irinotecan/cisplatin), in female CD-1 nude mice implanted with human small-cell lung cancer (SCLC) cells. Compared to liposomes, polymeric NPs have several advantages such as higher stability, higher sustained controlled drug-release profiles, higher loading capacity for poorly watersoluble drugs, and higher versatility since they can be tailored for specific requirements. Polymeric NPs consist of amphiphilic diblock copolymers autoassembling in aqueous solutions that allow simultaneous delivery of both hydrophilic, e.g., DOX, and hydrophobic, e.g., docetaxel, molecules.66 The temporal control on drug release by using nanoscale-based dual drug delivery system has been exploited by combining a chemodrug, DOX, with an antiangiogenic agent, combretastatin.67

(Pt) present in cisplatin molecule forming glutathione−Pt complex which is excreted out of the cells via ATP dependent glutathione-S-conjugate export pump or via the MRP2;11 (iv) metallothioneins (MTs) that bind and complex a number of trace metals contained in antineoplastic drugs, such as cisplatin, melphalan, bleomycin, and cytarabine,17−20 and negatively regulate apoptosis;21 (v) the DNA topoisomerase II enzyme (Topo II) whose DNA damage function altered by cancer cells confers resistance to drugs including doxorubicin (DOX), actinomycin D, mitoxantrone, etoposide, teniposide, etc.;13,22 (vi) detoxification enzymes, such as cytochrome p450, that rapidly metabolize and inactivate the internalized drugs;23 (vii) catalytic enzymes, such as dihydropyrimidine dehydrogenase and thymidylate synthase, that reduce efficacy of 5-fluorouracil (5-FU) and methotrexate;24−27 (viii) antiapoptotic proteins, such as survivin and Bcl-2 family members, that can be upregulated by cancer cells,13,28 and tumor suppressor gene (p53) that can be deleted in a variety of tumors.5 To circumvent the MDR process cancer chemotherapy has become progressively sophisticated in recent years: it is combined with other approaches, such as surgery, radiation, antibody-blocking therapy,29 the use of high doses or high dosing frequency of the drugs, and the use of multiple drugs with different molecular targets30 or inhibitors of transporters involved in drug efflux administrated along with chemotherapy molecules.31 However, these approaches are far from perfect since they result in increasing severe side effects due to the lack of selectivity that intrinsically characterizes chemotherapy. Therefore, it is very necessary to explore, discover, and design new strategies able to overrule the MDR as well as the chemotherapy side effects. Recently, researchers have indicated the use of nanomaterials (NMs) or the modulation of autophagy as exploitable tools for counteracting MDR.32−35 Autophagy modulation NM-mediated is becoming an appealing opportunity in nanomedicine. In fact, literature data demonstrate that engineered NMs can impact positively and negatively on the autophagy process.36,37 The focus of this review is to collect the recent published literature about the relationship between MDR reversal and autophagy or NMs, pointing to hypothesize a role of autophagy perturbation induced by NMs in overcoming MDR.

2. NANOMATERIALS AS NEW FRONT LINE TO REVERSE CANCER MDR Nanomaterials (NMs) consist of nanoscale (1−100 nm) constructs, synthesized from organic and inorganic materials, defined by European Commission on 18 October 2011 as “A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm −100 nm. In specific cases and where warranted by concerns for the environment, health, safety or competitiveness, the number size distribution threshold of 50% may be replaced by a threshold between 1 and 50%.”38 Due to their sizes well matching intracellular molecules and structures, NMs provide a range of devices useful in cancer management, i.e., cancer diagnostic and therapy. The greatest impact of nanotechnology in cancer focuses the realm of specific drug/ gene delivery39 and the rapid and sensitive detection of cancerrelated molecules by enabling detection of ill cells even when molecular changes occur only in a small percentage of cellular population.40 In fact, nanoscale constructs, belonging to NMs, B



Review

Table 1. Examples of Nanosized DDSs Counteracting MDRa in vivo model

nanosized DDS

molecules delivered

cell lines

liposomes PLGA-NPs liposomes MSNPs cationic core−shell NPs PLGA-NPs liposomes MNPs/PAMAM PEG-coated liposomes K237-NPs

6-mercaptopurine daunorubicin paclitaxel/tariquidar DOX/verapamil DOX/siRNA paclitaxel/siRNA paclitaxel/siRNA DOX/siRNA asODN oxaliplatin paclitaxel

Jurkat Hut 76 JC NCI-ADR-RES K562 KB-V1 MDA-MB-231 JC H69AR MCF-7 MDA-MB-435 HepG2

BALB/c mice bearing JC tumors

mice bearing B16BL6 melanoma xenografts HCT-15 mice

type of cancer

refs

leukemia breast ovarian carcinoma leukemia cervix carcinoma breast breast lung breast breast liver melanoma colorectal adenocarcinoma

87 88 89 90 91 92 93 94 95 96

a PLGA-NPs, poly(lactic-co-glycolic) acid nanoparticles; MSNPs, mesoporous silica nanoparticles; MNPs, magnetic nanoparticles; PAMAM, polyamidoamine dendrimers; PEG, polyethylene glycol; K237-NPs, nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides; DOX, doxorubicin; siRNA, small interfering RNA; asODN, antisense oligonucleotide.

activation of autophagy supports a protection mediating acquired resistance phenotype of some cancer cells during chemotherapy, but, on the other hand, autophagy can be a death executioner.99 Autophagy represents cell response to stress and consists in the lysosomal degradation and/or recycling of the cytoplasmic material.100 Autophagy has different end purposes: (i) to control quality and to remove harmful intracellular macromolecular aggregates and/or organelles101,102 often associated with aging and degenerative diseases;103,104 (ii) to replenish amino acid pools and energy during starvation as well as to ensure energetic homeostasis and supply anabolic precursors in cells stimulated to proliferation by oncogenes by digestion of proteins;105 (iii) to cooperate with molecular machineries and organelles in the cell death/cell survival balance;104 (iv) to regulate and ignite innate and adaptive immunity and inflammation;106,107 (v) to support protein secretion and trafficking of integral membrane proteins, involved in tissue development, remodeling, and inflammation, to the plasma membrane.108 The autophagy process is regulated by autophagy-related genes (ATGs)109 and consists of five phases, i.e., initiation, elongation, closure, maturation, and degradation, each regulated by different complexes (Figure 1).110 Autophagy is induced or inhibited by multiple sensors, such as mammalian target of rapamycin (mTOR), Beclin-1, p53, Ras, class I PI3K, class III PI3K, LKB1/AMPK, ER stress response, and microRNA (miRNAs).111,112 Specifically, exploitation of autophagy in chemotherapy trials can improve the killing efficacy of drugs. The strategies can include combination of chemotherapy and autophagy inhibitors, resensitization of the chemoresistant cells to drugs, and driving the apoptosis-defective cancer cells toward death.113 More important, autophagy can also play a pivotal role in antitumor immune cell metabolism by controlling cancer progression,114 providing immunogenic tumor antigens, increasing the efficiency of cross presentation, and regulating antigen delivery by releasing autophagosomes.115,116 Several reports have shown that autophagy has a dual role in MDR: it may lead to survival of MDR tumors, or its activation may lead to cancer cells’ death. Thus, the inhibition of autophagy can resensitize previously resistant cancer cells and augment cytotoxicity of chemotherapeutic agents, whereas the promotion of autophagy has a prodeath role under certain circumstances and following treatment with a specific set of chemotherapeutic agents, either

In recent years, polymethacrylate-based copolymers, commercially known as Eudragit, have been used to prepare microcapsules and nanoformulations to improve the solubility of poorly water-soluble drugs. Eudragit, a family of anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives, is mainly exploited to deliver drugs, also chemotherapics such as genistein,68 valdecoxib,69 oxaliplatin,70 and curcumin,71,72 to colon and stomach.73 The resistance of cancer cells to cytotoxic drugs is one of the major causes of the failure of cancer chemotherapy. Since cytotoxic drugs’ concentration and availability in cytosol and nucleus strictly dictate the outcome of cancer chemotherapy, many efforts have been made to develop inhibitors of the several proteins and enzymes involved in MDR mechanism.8,9,74 Unfortunately, inhibitors display a lot of disadvantages: no specificity toward the target sites, cardiotoxicity, nephrotoxicity, neurotoxicity, altered pharmacokinetics, and biodistribution of coadministered anticancer drugs. The use of NMs can avoid these side effects. In particular, several kinds of NMs can be used to design nanosized DDSs able to simultaneously encapsulate or attach ligands or antibodies targeting MDR tumor cells,75,76 chemotherapy drugs, nucleic acids,77 and MDR proteins and enzyme inhibitors.78 The main features characterizing an optimal DDS for overcoming MDR are (i) to evade or inhibit drug efflux pumps,79−82 (ii) to shield cytotoxic drugs from cytoplasmic detoxification enzymes,83 and (iii) to inhibit nutrients (glucose, minerals, and growth factors) and oxygen blood supply via interaction with tumor endothelial cells (TECs) which provide life support to MDR tumor cells.84−86 Examples of nanosized DDSs counteracting MDR are reported in Table 1.

3. ROLE OF AUTOPHAGY IN CIRCUMVENTING MDR It is increasingly evident that in many pathological conditions (infections, neurodegeneration, aging, Crohn’s disease, heart disease, cancer) autophagy is deregulated.97 In particular, the strict connection between cancer and autophagy is supported by the numerous oncogenes and oncosuppressor proteins that regulate both processes.98 Albeit the effects of autophagy (inhibition and induction as well) on cancer occurrence, progression, and regression are not yet completely clarified, nonetheless autophagy can be considered a new target for cancer therapy.99 Indeed, due to its potential to either induce cell death or promote cell survival, autophagy plays a paradoxical role during anticancer treatments. On one hand, C



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Figure 1. Nanomaterial-induced autophagy. NMs can interact with autophagy at different steps of the process. In particular, they affect autophagy signaling pathways via (1) induction of oxidative stress-dependent signaling (e.g., ER and mitochondria stress), (2) suppression of Akt-mTOR signaling, and (3) alteration of autophagy related gene/protein expression (e.g., Atg5). Autophagy occurs through a four multistep process: (1) initiation (or nucleation), (2) elongation, (3) closure/maturation, and (4) fusion/degradation. These steps occur irrespective of whether autophagy has been induced through stress/damaged proteins and organelle accumulation, or through starvation. Nucleation complex formation is the first step of autophagy: the membrane of endoplasmic reticulum (ER), mitochondria, Golgi, and plasma membrane contribute to the formation of phagophores, initial isolated limiting membrane of autophagosomes. Two complexes regulate the initiation phase of autophagy: the ATG1/unc-51like kinase (ULK) complex, including ATG13 and FIP200, and the Vps34-Atg6/beclin1 class III PI3-kinase complex. Later steps of autophagy, i.e., autophagosome elongation, expansion, and closure, are regulated by two ubiquitylation-like conjugation systems, Atg5-Atg12-Atg16 and LC3-PE complex; Atg7 and Atg10 and Atg3, Atg4, and Atg7 regulate the two complexes’ formation, respectively. These complexes continuously transport lipids and LC3 to isolation membrane elongating the double-membrane structure that, in turn, sequesters target materials with cytosol matrix forming the autophagosome after its closure. When the autophagosome is completed, it fuses with the lysosome to form an autophagolysosome, where the cytosolic cargo is degraded via the lysosomal acidic hydrolases. In the lysosome, hydrolytic enzymes digest the contents and inner membrane of the autophagosomes, with autophagic machinery (i.e., LC3), recycled through the cytoplasm for recruitment to other nascent autophagosomes. Cytoskeleton mediates protein trafficking during autophagosome formation.

by enhancing the induction of apoptosis or autophagydependent cell death. Increasing in vitro and in vivo evidence shows that autophagy inhibition augments cytotoxicity of several anticancer drugs by counteracting the prosurvival outcome of autophagy.113 The most common autophagy inhibitors impair the formation of autophagosomes (3-methyladenine, 3-MA, and wortmannin), the acidification of lysosomes (chloroquine, CQ, and hydroxychloroquine, HCQ), and the fusion of autophagosomes with lysosomes (bafilomycin A1, BafA). The only approved autophagy inhibitors, showing effectiveness and safety in clinical trials, are CQ and HCQ. Modulators of autophagy may be used beneficially as adjuvants during the treatment of cancers. siRNAs can be used to silence gene promoting autophagymediated cell survival.

Table 2 summarizes the molecules exploitable in reversal of MDR since they are able to promote prodeath autophagy or inhibit prosurvival autophagy. When tumor cells become resistant to chemotherapy drugs, a number of compounds that elicit a prodeath role of autophagy by interacting at different levels of the process contribute to efficacy of anticancer drugs and can be exploited to reverse MDR. Suberoylanilidehydroxamic acid (SAHA), a prototype of the newly developed histone deacetylase (HDAC) inhibitors, inhibits proliferation of tamoxifen estrogen receptor-positive breast cancer patients-resistant MCF-7 (TAMR/MCF-7) cells, reduces the expression of HDAC1, 2, 3, 4 and 7, and induces autophagy-associated cell death. Moreover, in mice bearing TAMR/MCF-7 cell xenografts, SAHA significantly reduces tumor growth and weight, without apparent side effects.117 NVP-BEZ235, a dual PI3K and mTOR inhibitor, negatively D



Review

Table 2. Examples of Molecules Promoting Autophagic Prodeath Outcome or Inhibiting Autophagic Process Exploitable in Reversal of MDRa molecules

target

SAHA

HDAC inhibitor

NVP-BEZ235

PI3K/Akt/mTOR inhibitor

Mono-Pt

AKT1-MTOR-RPS6KB1 pathway MAPK1 (ERK2)/MAPK3 (ERK1) signaling oxidative stress

cannabinoids/ GEM imatinib VOA

Bcr-Abl kinase c-kit PDGF Pgp

β-elemene OMP

vATPase oxidative stress p38 MAPK

PP2 5-FU/3-MA 5FU/Atg7siRNA 5-FU/CQ

SFK inhibitor thymidilate synthase inhibitor

gossypol VCR, DDP, THP, VP-16

effect on autophagic proteins/process

cell lines

Promoting Autophagic Cell Death reduction of HDAC 1, 2, TAMR/MCF-7 3, 4, 7 expression activation of autophagic NTUB1 N/P(14) subline flux enhanced ratio LC3-II/ Caov-3 LC3-I. NF-κB PaCa44, PaCa3, Panc1, CFPAC1, T3M4MiaPaCa2 inhibition of PDGF SLK-DOX phosphorylation enhanced ratio LC3-II/ U-2 OS/DX LC3-I mTOR inhibition MCF-7

thymidilate synthase inhibitor

pH lysosomes MiaPaCa-2 ASPC-1 Inhibiting Autophagy Ras-NIH 3T3/Mdr formation of colon26 HCT116 DLD-1 autophagosomes DLD-1/5-FU acidification of lysosomes HT-29

p53

modulation of p53 status

Ras-NIH 3T3/Mdr SKOV3

in vivo model xenografts TAMR/ MCF-7 mice

xenografts PaCa44 mice

xenografts S-180 sarcoma mice

xenografts DLD-1 mice xenografts colon26 BALB/c mice

type of cancer

refs

breast

117

urothelial carcinoma ovarian

118

pancreatic

120

Kaposi’s sarcoma osteosarcoma

121

breast

123

pancreas

124

colon colon

ovarian carcinoma

119

122

125 126, 127 128, 129 130 131

a

SAHA, suberoylanilidehydroxamic acid; HDAC, histone deacetylases; Mono-Pt, monofunctional platinum(II) complex; GEM, gemcitabine; VOA, vocamine; OMP, omeprazole; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; 5-FU, 5-fluorouracil; 3-MA, 3 methyladenine; CQ, chloroquine; VCR, vincristine; DDP, cisplatin; THP, pirarubicin; VP-16, etoposide; Pgp, P-glycoprotein.

(vATPase) causing autophagy in MiaPaCa-2 and ASPC-1 human pancreatic cancer cells. This effect drives cell death and circumvents common drugs’ resistance mechanisms of pancreatic cancer cells. 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a selective Src family tyrosine kinase (SFK) inhibitor, is antiproliferative in multidrug-resistant v-Ha-rastransformed NIH 3T3 cells (Ras-NIH 3T3/Mdr) by arresting cell-cycle at G1/S without apoptosis induction and by depressing autophagy.125 3-MA or Atg7 siRNA significantly augments 5-FU-induced apoptosis in several human colon cancer cell lines (colon26 and HT29, HCT116, DLD-1, and DLD-1/5-FU, a specific 5-FU-resistant subline). This synergistic effect of 5-FU and 3-MA is further confirmed in the DLD1 xenograft tumor model.126,127 5-FU inhibits the proliferative activity of HT-29 human colon cancer cells by mainly arresting the cells in the G0/G1-phase and also partially inducing apoptosis. This effect is potentiated by CQ pretreatment, that, by inhibiting the autophagic process induced by 5-FU, potentiates anticancer effect of 5-FU.128 On the other hand, 5-FU induces autophagic cell death in apoptosis defective Bax(−/−) and PUMA(−/−) colon cancer HCT116 by decreasing mTOR activity.132 The use of 5-FU/CQ combination is efficacious in vivo; in fact, CQ inhibits 5-FU-induced autophagy, enhances 5-FU-induced inhibition of tumor growth into BALB/c mice injected subcutaneously with colon 26 cancer cells, and significantly increases apoptosis and Bad and Bax expression compared with other treatments.129 Defective autophagy accelerates necrosis and apoptosis in response to gossypol, a natural BH3 mimetic found in cottonseeds, in the vHa-ras-transformed NIH 3T3 cells overexpressing P-glycoprotein (Ras-NIH 3T37Mdr).130

affects NTUB1 and cisplatin-resistant N/P(14) urothelial carcinoma cells proliferation by activating autophagy and cell cycle arrest without inducing apoptosis.118 Autophagy-dependent cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum(II) complex named Mono-Pt in Caov-3 human ovarian carcinoma cells, exerting anticancer effect via autophagy in apoptosis-resistant ovarian cancer.119 Addition of cannabinoids, a group of terpenophenolic compounds present in Cannabis possessing anticancer activities, improves gemcitabine (GEM, 2′,2′difluorodeoxycytidine) anticancer action in pancreatic adenocarcinoma cells by synergistically inhibiting cell growth and increasing reactive oxygen species (ROS). The antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines; thus the combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects.120 Imatinib, a tyrosine kinase inhibitor, also known as STI571 or Gleevec, overcomes MDR in Kaposi’s sarcoma cell line DOX resistant (SLK-DOX) by increasing autophagy.121 Meschini et al.122 demonstrated that the bisindolic alkaloid vocamine (VOA) isolated from the plant Peschiera f uchsiaefolia exerts a chemosensitizing effect on cultured MDR osteosarcoma DOX resistant cells U-2 OS/ DOX by inhibiting Pgp action. This cytotoxic effect depends on autophagy induction. 13,14-Bis(cis-3,5-dimethyl-1-piperazinyl)β-elemene, a novel β-elemene derivative, shows potent antitumor activities against human breast cancer MDR MCF7 cells. The cytotoxic function is associated with inhibition of mTOR that causes induction of autophagy allowing to arrest cancer cells’ proliferation.123 Recently, Udelnow124 demonstrated that omeprazole (OMP) modulates the lysosomal transport pathway via interaction with vacuolar proton pump E



Review

Table 3. A Summary of NM-Mediated Autophagy in Cancer Treatmenta DDS nC60 nC60 C60(Nd) NPs COOH-CNTs Fe@Au-NPs FeO-NPs CQ-Au-NPs CuO-NPs

molecules delivered DOX

effect on autophagic process ERK activation Atg5 mTOR S6 Akt mitochondria damage mitochondria damage

C225-NPs MnO magnetic nanocrystals nano Nd2O3

anti-EGFR antibody DOX

autophagosome formation EGFR pathway p53

nanoliposomal C6ceramide α-Al2O3-NPs

vinblastine

autophagosome formation vacuole accumulation

PLGA-NPs

antigens tumor derived docetaxel/3-MA/CQ

cell lines

in vivo model

C6 U251 HeLa MCF-7 MCF-7 A549 OEMC1 A549 MCF-7 A549 NSCLC HepG2 HeLa

S180 tumor bearing mice

NCI-H460 HepG2 LS174T

MCF-7

xenografts LS174T mice C57BL/6 mice bearing 3LL tumor xenograft SCID mice

type of cancer

refs

glioma cervix breast breast lung adenocarcinoma oral lung adenocarcinoma breast lung adenocarcinoma

133 134 135 136 137 138 139 140

non-small cell lung hepatocarcinoma cervix non-small cell lung

141 142

hepatocarcinoma colon lung

144 145

breast

146

143

a

nC60, fullerene water suspension; nC60(Nd) NPs, nC60 derivative; DOX, doxorubicin; COOH-CNTs, carboxylic acid carbon nanotubes; Fe@AuNPs, iron core and gold shell nanoparticles; FeO-NPs, iron oxide nanoparticles; CQ-Au-NPs, chloroquine-gold nanoparticles conjugated; CuO-NPs, copper oxide nanoparticles; C225-NPs, magnetic NPs; nano Nd2O3, nanosized neodymium oxide; α-Al2O3-NPs, alumina oxide nanoparticles; PLGA-NPs, poly(lactic-co-glycolic) acid nanoparticles.

interfering with Akt-mTOR signaling,130,149 and by altering autophagy related gene/protein expression and/or regulation.134 The interactions of NMs with the different phases of autophagy are reported in Figure 1. The increase in autophagosomes upon NM interaction may be an adaptive response of the cells to sequester and degrade these materials following their cytoplasm entrance. In fact, cells perceive NMs like pathogen that must be removed, likely through ubiquitination mechanism.150 Among various kinds of NMs, fullerene C60 and its derivatives, carbon nanotubes (CNTs), iron (Fe)- and alumina (Al)-related NPs, and rare earth oxide NMs are able to interact with autophagy in cancer cell lines. Due to their unique properties in thermal stability, conductivity, and mechanical and optical performance, carbon-based NMs are very important in biomedicine research. In particular, they play a potential role in the treatment of cancer by triggering autophagy. For example, the C60 fullerene water suspension (nC60) reduces the proliferation of rat glioma cell line C6 and the human glioma cell line U251 in a dose-dependent manner. In particular, a low dose of nC60 (0.25 μg/mL) causes oxidative stress/ERKindependent cell cycle block in G(2)/M phase and subsequent inhibition of tumor cell proliferation. This effect depends on the induction of autophagy, as demonstrated by using the specific inhibitor BafA1. The fact that primary astrocytes are less sensitive to cytostatic action of nC60 suggests a possible tumor-specific targeting.133 Also, it has been demonstrated that nC60 is capable of overruling resistance to killing in MCF-7 drug resistant breast cancer cells. In fact, nC60 at noncytotoxic concentrations causes autophagy requiring functional Atg5 gene and sensitizes DOX killing of both normal HeLa and drug-resistant MCF-7 cancer cells in a ROS-dependent and photoenhanced manner.134 In addition, nC60 derivative is also able to kill MCF-7 drug-resistant cancer cells by modulating autophagy, and its potential in inducing autophagy and sensitizing chemotherapy killing of MCF-7 cells is greater than that of nC60.135 Three types of functionalized single-walled

A pivotal role in the regulation of MDR is played by p53, which can also modulate autophagy. Recently, Kong and colleagues131 established cell models with different p53 status by transfecting wild-type p53 (wt p53) and mutant 175H p53 constructs to human ovarian carcinoma SKOV3 and multidrug resistant SKVCR cell lines. So, they demonstrated the influence of different p53 status on drug sensitivity to vincristine (VCR), cisplatin (DDP), pirarubicin (THP), and etoposide (VP-16). VCR administered to SKVCR induces MDR and overexpression of Pgp and enhances autophagy compared with parental SKOV3. Wt p53 and 175H have no influence on drug sensitivity in SKOV3, while both sensitized SKVCR cells to VCR, THP, and VP-16. Wt p53 induced only apoptosis, while 175H triggers autophagy-dependent cell death, necrosis, and apoptosis and reverses MDR.

4. NM-INDUCED AUTOPHAGY: CAN IT BE EXPLOITED IN MDR REVERSAL? As above-reported, a plethora of studies have shown that NMs and autophagy could be exploited for reversal of resistance to death pathways occurring upon certain chemotherapy protocols. Conversely, no direct data regarding a NM-based autophagy counteracting specifically mechanism involved in MDR are present. Some evidence concerning the impact of NMs on autophagy in cancer cell lines, both drug resistant and not, could suggest a role of NM-induced autophagy in MDR reversal. Table 3 summarizes the NMs, used alone or in combination with different molecules, able to counteract cancer cells’ proliferation and/or survival via autophagy induction. Autophagy is a new emerging cellular effect of NMs, and various kinds of NMs are able to interact with the autophagic process. It is important to emphasize that NMs impact the autophagic pathways depending on the nature of the material, the cell type, the culturing conditions,147,148 and the data in the literature are very contradictory in this regard. Conversely, it is well-known that NMs can interfere with autophagic pathways by inducing oxidative stress-dependent signaling,133,137,138 by F



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ceramide, and an autophagy maturation inhibitor, vinblastine, synergistically enhances apoptotic cell death in human hepatocarcinoma (HepG2) and human colon (LS174T) cancer cell lines. Combination treatment increases autophagic vacuole accumulation and decreases autophagy maturation, without reduction of the autophagy flux protein P62. In human colon cancer xenograft model (LS174T), a single intravenous injection of the drug combination significantly decreases tumor growth without induction of toxicity. Additionally, Beclin-1 knockout suppresses combination treatment-induced cell death in vitro, supporting that the antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination is mediated by targeting the autophagic pathway via blockade of prosurvival autophagy.144 In recent years the therapeutic cancer vaccination is becoming an attractive strategy, since it improves T cells’ recognition of ill cells in cancer patients. α-Al2O3-NPs can act as an antigen carrier by exploiting the autophagic process since they can overcome the difficulty to generate large numbers of T cells able to recognize cancer cells’ antigens using conventional vaccine carrier systems. α-Al2O3-NPs can be designed to deliver antigens to autophagosomes in dendritic cells, that in turn present these antigens to T cells through autophagy. Immunization of C57BL/mice bearing experimental metastasis 3LL lung tumors by using dendritic cells pulsed with α-Al2O3NPs conjugated to autophagosomes boosts T cells’ response and induces tumor regression.145 Finally, NMs can also hinder the advantages of the nanomedicine by triggering autophagy. In fact, PLGA-NPs delivering docetaxel anticancer drug were sequestered into autophagosomes and degraded into lysosomes allowing cells to resist the death. The combination of NP formulation with autophagy inhibitors such as 3-MA and CQ enhances the therapeutic effect of docetaxel both in MCF-7 cells and in xenograft SCID mice model.146

carbon nanotubes (f-SWCNTs) have been studied by Liu et al.136 in order to evaluate if cytotoxicity triggered via autophagy can be exploited in cancer management. They considered carboxylic acid (COOH-CNTs), poly-aminobenzenesulfonic acid CNTs (PABS-CNTs), and polyethylene glycol (PEGCNTs) CNTs and demonstrated that only COOH-CNTs induce autophagic cell death in human lung adenocarcinoma A549 cells by decreasing phosphorylation levels of mTOR, mTOR’s substrate S6, and Akt. Moreover, COOH-CNTs induce cell death in the epithelial cells of the lung of male BALB/c mice. These results strongly highlight that the functionalization of the NM surface can induce autophagy and, thus, it can be considered in cancer treatment. Cytotoxic action toward cancer but not normal cells is also displayed by metal-based NMs, such as Fe-, Al-, and Cu and their relative oxide and Au- NPs. In particular, NPs with an iron core and gold shell (Fe@Au-NPs) have been reported to limit proliferation of oral cancer OECM1 cells through mitochondria-mediated autophagy. Fe@Au-NPs cause an irreversible membrane-potential loss in the mitochondria of cancer cells, but only a transitory decrease in membrane potential in healthy control cells accompanied by production of ROS. Addition of ROS scavengers does not protect cancerous cells from the Fe@ Au-NP-induced cytotoxicity.137 Iron oxide (FeO)-NPs selectively induce autophagy in human lung epithelial cancer cells (A549) but not in normal human lung fibroblast cells (IMR90), correlated with ROS production and mitochondrial damage, thus demonstrating that FeO-NPs are a promising tool in biomedicine for their ability to induce autophagic cell death in cancer cells since pretreatment of cancer cells with 3MA allows protection against autophagy and promotion of cell viability.138 CQ-Au-NPs elicit anticancer action through inhibition of cancer cell growth in MCF-7 cells by eliciting necrotic cell death mediated by autophagy induction.139 Sun and co-workers140 demonstrated the induction of autophagic cell death, following culture in the presence of CuO-NPs, in human adenocarcinoma A549 cells, but not in human nonsmall cell lung cancer H1650 cells and human nasopharyngeal carcinoma CNE-2Z cells demonstrating that the response to NMs strictly depends on cell type. The nanoscale three-dimensional arrangement of anti-EGFR antibody by using magnetic NPs (C225-NPs), consisting of a paramagnetic iron core surrounded by a gold layer, produces a high antitumor activity by autophagic cell death in human nonsmall cell lung cancer (NSCLC) cells. In fact, C225-NP treatment regulates EGFR-signaling pathway, and the density of anti-EGFR antibody attached to NPs is crucial in C225-NPmediated tumor cell killing.141 MnO magnetic nanocrystals elicit p-53-activation-independent autophagic cell death in vitro, by using HepG2 and HeLa cells, and in vivo, by using sarcoma 180 (S180) tumor bearing mice, contributing to enhance the effect of DOX on killing cancer cells.142 Rare earth oxide NMs are able to elicit autophagy and cell death in several cancer cell lines. For example, nanosized neodymium oxide (nanoNd2O3) induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCIH460 cells at micromolar equivalent concentration range. Autophagy induced by nanoNd2O3 is accompanied by S-phase cell cycle arrest, mild disruption of mitochondrial membrane potential, and inhibition of proteasome activity.143 Recently, it has been demonstrated that a combination therapy with an autophagy inducer, nanoliposomal C6-

5. CONCLUSIONS Cancer is a major cause of mortality in the modern world, with more than 10 million new cases every year. Therefore, there is an urgent need for more effective and valuable anticancer regimens able not only to kill cancer cells but also to reduce the impact of the therapies on healthy tissues and to circumvent defense mechanism acquired by tumor cells, known as MDR, an intricate and dynamic phenomenon affecting chemotherapy effectiveness in cancer patients. Cancer cells survive or become resistant to treatment against a wide variety of drugs. Among novel smart approaches exploitable in cancer counteracting, NM-based DDSs and autophagy mechanism are under investigation. NMs by incorporating or conjugating drugs are very promising since they circumvent insufficient drug retention into the cells and allow their precise targeting. In parallel, autophagy seems to be also very promising in MDR reversal. In fact, data in vivo and in vitro support the idea that both autophagy inhibition and induction could play an important role in cancer management, including MDR reversal. In fact, autophagy inhibition may potentiate the resensitization of therapy-resistant cancer cells to the anticancer drugs. The combination of autophagy inhibitors with cytotoxic drugs is currently attracting much attention. In parallel, promoting the prodeath role of autophagy is very important to kill cells displaying resistance to apoptosis. In finding new strategies to circumvent MDR, the synergy existing between autophagy modulation and NMs could represent the last frontiers of G



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(8) Choi, C. H. ABC Transporters as Multidrug Resistance Mechanisms and the Development of Chemosensitizers for Their Reversal. Cancer Cell Int. 2005, 4, 5−30. (9) Wang, R. B.; Kuo, C. L.; Lien, L. L.; Lien, E. J. Structure-Activity Relationship: Analyses of P-Glycoprotein Substrates and Inhibitors. J. Clin. Pharm. Ther. 2003, 28, 203−228. (10) Zhou, S. F. Structure, Function and Regulation of PGlycoprotein and Its Clinical Relevance in Drug Disposition. Xenobiotica 2008, 38, 802−832. (11) Borst, P.; Evers, R.; Kool, M.; Wijnholds, J. A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins. J. Natl. Cancer Inst. 2000, 92, 1295−1302. (12) Toyoda, Y.; Hagiya, Y.; Adachi, T.; Hoshijima, K.; Kuo, M. T.; Ishikawa, T. MRP Class of Human ATP Binding Cassette (ABC) Transporters: Historical Background and New Research Directions. Xenobiotica 2008, 38, 833−862. (13) Zhang, B.; Liu, M.; Tang, H. K.; Ma, H. B.; Wang, C.; Chen, X.; Huang, H. Z. The Expression and Significance of MRP1, LRP, Topoiiβ, and BCL2 in Tongue Squamous Cell Carcinoma. J. Oral Pathol. Med. 2012, 41, 141−148. (14) Kickhoefer, V. A.; Rajavel, K. S.; Scheffer, G. L.; Dalton, W. S.; Scheper, R. J.; Rome, L. H. Vaults Are Up-Regulated in MultidrugResistant Cancer Cell Lines. J. Biol. Chem. 1998, 273, 8971−8974. (15) Dietel, M.; Arps, H.; Lage, H.; Niendorf, A. Membrane Vesicle Formation Due To Acquired Mitoxantrone Resistance in Human Gastric Carcinoma Cell Line EPG85-257. Cancer Res. 1990, 50, 6100− 6106. (16) Hazlehurst, L. A.; Foley, N. E.; Gleason-Guzman, M. C.; Hacker, M. P.; Cress, A. E.; Greenberger, L. W.; De Jong, M. C.; Dalton, W. S. Multiple Mechanisms Confer Drug Resistance To Mitoxantrone in the Human 8226 Myeloma Cell Line. Cancer Res. 1999, 59, 1021−1028. (17) Chin, J. L.; Banerjee, D.; Kadhim, S. A.; Kontozoglou, T. E.; Chauvin, P. J.; Cherian, M. G. Metallothionein in Testicular Germ Cell Tumors and Drug Resistance. Clinical Correlation. Cancer 1993, 72, 3029−3035. (18) Dziegiel, P.; Forgacz, J.; Suder, E.; Surowiak, P.; Kornafel, J.; Zabel, M. Prognostic Significance of Metallothione in Expression in Correlation with Ki-67 Expression in Adenocarcinomas of Large Intestine. Histol. Histopathol. 2003, 18, 401−407. (19) Kasahara, K.; Fujiwara, Y.; Nishio, K.; Ohmori, T.; Sugimoto, Y.; Komiya, K.; Matsuda, T.; Saijo, N. Metallothionein Content Correlates with the Sensitivity of Human Small Cell Lung Cancer Cell Lines to Cisplatin. Cancer Res. 1991, 51, 3237−3242. (20) Kondo, Y.; Woo, E. S.; Michalska, A. E.; Choo, K. H.; Lazo, J. S. Metallothionein Null Cells Have Increased Sensitivity to Anticancer Drugs. Cancer Res. 1995, 55, 2021−2023. (21) Shimoda, R.; Achanzar, W. E.; Qu, W.; Nagamine, T.; Takagi, H.; Mori, M.; Waalkes, M. P. Metallothionein Is a Potential Negative Regulator of Apoptosis. Toxicol. Sci. 2003, 73, 294−300. (22) Beck, W. T.; Danks, M. K.; Wolverton, J. S.; Kim, R.; Chen, M. Drug Resistance Associated with Altered DNA Topoisomerase II. Adv. Enzyme Regul. 1993, 33, 113−127. (23) Gottesman, M. M.; Fojo, T.; Bates, S. E. Multidrug Resistance in Cancer: Role of ATP-Dependent Transporters. Nat. Rev. Cancer 2002, 2, 48−58. (24) Lenz, H. J.; Leichman, C. G.; Danenberg, K. D.; Danenberg, P. V.; Groshen, S.; Cohen, H.; Laine, L.; Crookes, P.; Silberman, H.; Baranda, J.; Garcia, Y.; Li, J.; Leichman, L. Thymidylate Synthase mRNA Level in Adenocarcinoma Of the Stomach: a Predictor for Primary Tumor Response and Overall Survival. J. Clin. Oncol. 1996, 14, 176−182. (25) Shintani, Y.; Ohta, M.; Hirabayashi, H.; Tanaka, H.; Iuchi, K.; Nakagawa, K.; Maeda, H.; Kido, T.; Miyoshi, S.; Matsuda, H. New Prognostic Indicator for Non-Small-Cell Lung Cancer, Quantitation of Thymidylate Synthase by Real-Time Reverse Transcription Polymerase Chain Reaction. Int. J. Cancer 2003, 104, 790−795. (26) Yamachika, T.; Nakanishi, H.; Inada, K.; Tsukamoto, T.; Kato, T.; Fukushima, M.; Inoue, M.; Tatematsu, M. A New Prognostic

exploitation. In fact, an increasing number of data indicate how different types of NMs, in relation to the nature of the material, the cell type, and the culturing conditions, are able to modulate (induction and blockade) autophagy mechanisms resulting in turn in the improved killing of several cancer cells. Thus, a deep understanding of the relationship between NMs and autophagy in cancer regimens could be pivotal to fight MDR.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +390832298614. Fax: +390832298937. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED MDR, multidrug resistance; DDSs, drug delivery systems; NMs, nanomaterials; ABC, ATP-binding cassette; Pgp, Pglycoprotein; MRPs, MDR-associated proteins; BCRP, breast cancer resistant protein; LRP, lung-resistance related protein; GSTs, glutathione-S-transferases; MTs, metallothioneins; DOX, doxorubicin; 5-FU, 5-fluorouracil; NPs, nanoparticles; PDT, photodynamic therapy; siRNA, small interfering RNA; SCLC, small-cell lung cancer cells; TECs, tumor endothelial cells; ATGs, autophagy-related genes; mTOR, mammalian target of rapamycin; miRNAs, microRNA; 3-MA, 3-methyladenine; CQ, chloroquine; HCQ, hydroxychloroquine; BafA, bafilomycin; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; Ras-NIH 3T3/Mdr, multidrug resistant v-Ha-ras-transformed 3T3 cells; VCR, vincristine; DDP, cisplatin; THP, pirarubicin; VP-16, etoposide; SAHA, suberoylanilidehydroxamic acid; HDAC, histone deacetylase; TAMR/MCF-7, tamoxifen estrogen receptor-positive breast cancer patients-resistant MCF-7 cells; GEM, gemcitabine; ROS, reactive oxygen species; VOA, vocamine; OMP, omeprazole; vATPase, vacuolar proton pump; nC60, fullerene water suspension; CNTs, carbon nanotubes; C60, fullerenes; fSWCNTs, functionalized single-walled carbon nanotubes; COOH-CNTs, carboxylic acid carbon nanotubes; PABSCNTs, poly-aminobenzenesulfonic acid carbon nanotubes; PEG-CNTs, polyethylene glycol carbon nanotubes; Fe@AuNPs, iron core and gold shell nanoparticles; FeO-NPs, iron oxide nanoparticles; CuO-NPs, copper oxide nanoparticles; nano Nd2O3, nanosized neodymium oxide; α-Al2O3-NPs, alumina oxide nanoparticles; PLGA-NPs, poly(lactic-co-glycolic) acid nanoparticles

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REFERENCES

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