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Targeting multidrug resistance in cancer by natural chemosensitizers Ahmed R. Hamed1,2* , Nahla S. Abdel-Azim1, Khaled A. Shams1 and Faiza M. Hammouda1

Abstract

Background: Statistics on cancer incidence and mortalities indicate that this disease still has a fatal outcome for a majority of patients due to non-sufficient treatment. The options available for cancer treatment include chemotherapy, which still commands a leading position in clinical oncology. A major obstacle to successful chemotherapy is the development of cellular resistance to multiple structurally unrelated anticancer drugs. This phenomenon has been termed multidrug resistance (MDR), which occurs in a majority of cancer patients. MDR is mainly due to the overexpression of ABC transporters which extrude chemotherapeutic drugs outside of cancer cells. A plethora of synthetic chemosensitizers have been described during the past decades that block ABC transporter function to reverse their MDR. However, none of them reached clinical routine application as of yet. In this review, we highlight the potential of natural products derived from plants, marine organisms, fungi, and other sources as chemosensitizers to the targeted major ABC transporters (ABCB1, ABCC1, and ABCG2).

Conclusion: Natural compounds may serve as lead compounds for the development of novel ABC transporter inhibitors with improved pharmacological features that can be used as adjuvant therapy to enhance the efficacy of chemotherapeutic drugs against MDR.

Keywords: Cancer, Multidrug resistance, Chemotherapy, Chemosensitizers, P-glycoprotein

Introduction Cancer includes a group of diseases that are character- ized by abnormal and out of control spreadable cellular growth (Mbaveng et al. 2017). Causative agents of can- cers are either external such as tobacco consumption and infections; or internal such as immune conditions, genetic mutations, and hormonal imbalance. The inci- dence of cancer is not limited to developing countries but also to already developed ones and the burden of cancer affects both. According to the World Health Organization (WHO), malignant neoplasms are ranked the second leading cause of deaths worldwide after car- diovascular diseases. In 2012 alone, a global record of 14.1 million newly diagnosed cancer cases with 8.2 mil- lion deaths due to cancer were reported (Torre et al. 2015). Moreover, these estimates are expected to in- crease by 2030 to about 150% which constitute a ringing

alarm. These statistical estimates are based on GLOBO- CAN 2012 presented by the International Agency for Research on Cancer (IARC) (Torre et al. 2015; Society A.C 2016). Although the general term cancer covers many differ-

ent diseases, most types of cancers share a common fea- ture of not acting to available chemotherapies through development of multidrug resistance (MDR). MDR is a phenomenon by which cancer cells develop broad resist- ance to a wide variety of structurally and functionally unrelated compounds which may arise from several mechanisms of which the best described is the overex- pression of drug efflux proteins such as P-glycoprotein. This ultimately leads to cancer relapse and death in 90% of patients. Some cancers such as gastrointestinal and renal cancers are largely unresponsive to chemotherapy, i.e., they have a high degree of intrinsic MDR, whereas leukemias, lymphomas, ovarian, and breast cancers often respond to initial treatment, but then acquire MDR dur- ing the course of the disease. MDR to anticancer drugs is therefore a serious health problem that dramatically affects the efficacy of cancer treatments.

* Correspondence: [email protected] 1Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt 2Biology Unit, Central Laboratory for Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt

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Hamed et al. Bulletin of the National Research Centre (2019) 43:8 https://doi.org/10.1186/s42269-019-0043-8

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In this article, we review the possible mechanisms of multidrug resistance with focus on efflux transporters- related MDR. We also emphasize how natural products constitute a promising value as chemosensitizers through inhibition of different efflux proteins.

Mechanisms of drug resistance in cancer The cancer treatments available to patients include chemotherapy, radiotherapy, surgery, immunotherapy, or a combination of them (Gottesman et al. 2002; Saeed et al. 2016; Saluja et al. 2016; Nie et al. 2016). Although many cancer types are curable with chemotherapeutic cytotoxic agents, sometimes chemoresistance against cancer thera- peutic agents develops. Chemoresistance against drugs can be either “intrinsic” which describe the pre-existing constitutive overexpression of cancer cell detoxification system before the start of chemotherapeutic regimen, or “acquired” where it develops after the start of the chemo- therapy over time or after a secondary chemotherapy with tumor relapse (Gottesman 2002; Quintieri et al. 2007). The mechanisms through which cancer chemotherapy fails include pharmacological, physiological, and/or cellu- lar mechanisms (Sikic 2015). First, the pharmacological mechanisms of chemotherapy failure may include insuffi- cient drug dosing, or suboptimal dosing regimens of the chemotherapeutic regimens (Sikic 2015; Marangolo et al. 2006; Carlson and Sikic 1983). Second, the physiological mechanisms of chemother-

apy failure, however, include lack of optimal distribution of the chemotherapeutic agents to what is called “sanc- tuary sites” due to the presence of the blood-brain

barrier (at the central nervous system) and blood-tes- ticular barrier (at testes) (Fromm 2004). Another physiological mechanism for the chemother-

apy failure is the poor distribution of the chemothera- peutic agent to cancer tissue due to the poor vasculature in angiogenesis process (Kyle et al. 2007). Therefore, the use of anti-angiogenic agents (e.g., sunitinib) helped pa- tients to revert vasculature back to normal and im- proved the distribution of chemotherapeutic drug to their target cancer tissues (Matsumoto et al. 2011). Third, the cellular mechanisms involved in the chemo-

therapy resistance and eventually failure are schematic- ally outlined in Fig. 1.

Multi-drug resistance: a specific type of resistance A specific form of cellular drug resistance in cancer is termed multi-drug resistance (MDR).This is a phenomenon by which cancer cells become cross-resistant to a wide var- iety of structurally and pharmacologically unrelated cancer cytotoxic drugs such as vinblastine, paclitaxel, and doxorubicin (Callies et al. 2016; Wu et al. 2014; Kuete and Efferth 2015; Eichhorn and Efferth 2012). MDR renders the tumor cells non-responsive to treat- ment and failure of chemotherapy in 90% of meta- static cancers (Bernardes de Andrade Carli et al. 2013; Turk et al. 2009; Longley et al. 2006). The main mechanism describing MDR in cancer is the

overexpression of ATP binding cassette (ABC) transporter proteins that effectively efflux diverse chemotherapeutic agents outside the cancer cells, decreasing the intracellular drug concentration, rendering chemotherapy ineffective

Fig. 1 Cellular drug resistance mechanisms, adapted from (Sikic 2015) under permission from Elsevier Inc

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 2 of 14

(Fig. 2) (Saraswathy and Gong 2013; Yan et al. 2014; Krishna and Mayer 2000; Gillet et al. 2007; Kadioglu et al. 2016).

ABC transporters in normal physiology and cancer There are 49 ABC transporter genes in the human genome (Huang 2007; Gottesman and Ambudkar 2001; Glavinas et al. 2004). In normal physiology, these transporters actively transport endogenous and exogenous substrates through biological membranes into body tissues, such as small intestine, colon, kid- ney, pancreas, blood-brain barrier, and blood-testes barrier by ATP hydrolysis (Fromm 2004; Abdallah et

al. 2015). In addition to the detoxification of xenobi- otics, efflux transporters have a role in mediating the transport of some substrates across the cellular mem- branes such as cholesterol, amino acids, sugars, lipids, peptides, hydrophobic drugs, and antibiotics (Gottes- man and Ambudkar 2001; Dean and Annilo 2005; Ifergan et al. 2004; Shi et al. 2007a; Shi et al. 2007b). However, in cancer cells, some of these transporters are responsible for chemotherapy failure. The identified human drug transporter protein super-

family is divided into seven sub-families: namely ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, and ABCG (Katha- wala et al. n.d.) with diverse physiological functions and roles in multidrug resistance (Table 1).

Fig. 2 Schematic representation of MDR in cancer cells with ABC transporter-mediated drug efflux. Adapted from (Avendaño and Menéndez 2015) under permission from Elsevier Inc

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 3 of 14

Table 1 Families of human ABC transporters and their functions. Data were adapted from Vasiliou et al. (2009)

ABC transporter family ABC transporter Major function

ABCA ABCA1 Efflux of cholesterol

ABCA2 MDR

ABCA3

ABCA4 Efflux of N-retinylidene-phosphatidylethanolamine (PE)

ABCA5 Urinary diagnostic marker for prostatic intraepithelial neoplasia (PIN)

ABCA6 MDR

ABCA7 Efflux of Cholesterol

ABCA8 Transports of some lipophilic drugs

ABCA9 Might play a role in monocyte differentiation and macrophage lipid homeostasis

ABCA10 Cholesterol-responsive gene

ABCA12 Has implications for prenatal diagnosis

ABCA13 Inherited disorder affecting the pancreas

ABCB ABCB1 MDR

ABCB2-TAP1 Peptide transport

ABCB3-TAP2 Peptide transport

ABCB4 Phosphatidylcholine (PC) transport

ABCB5 Melanogenesis

ABCB6 Iron transport

ABCB7 Fe/S cluster transport

ABCB8 Intracellular peptide trafficking across membranes

ABCB9 Located in lysosomes

ABCB10 Export of peptides derived from proteolysis of inner-membrane proteins

ABCB11 Bile salt transport

ABCC ABCC1 MDR

ABCC2 Organic anion efflux

ABCC3 MDR

ABCC4 Nucleoside transport

ABCC5 Nucleoside transport

ABCC6 Expressed primarily in liver and kidney

ABCC7-CFTR Chloride ion channel (same as CFTR gene in cystic fibrosis)

ABCC8 Sulfonylurea receptor

ABCC9 Encodes the regulatory SUR2A subunit of the cardiac K(ATP)channel

ABCC10 MDR, xenobiotic efflux

ABCC11

ABCC12

ABCC13 Encodes a polypeptide of unknown function

ABCD ABCD1 Transport of Very long chain fatty acid (VLCFA)

ABCD2 Major modifier locus for clinical diversity in X linked ALD (X-ALD)

ABCD3 Involved in import of fatty acids and/or fatty acyl coenzyme as into the peroxisome

ABCD4 May modify the ALD phenotype

ABCE ABCE1 Oligoadenylate-binding protein

ABCF ABCF1 Susceptibility to autoimmune pancreatitis

ABCF2 Tumor suppression at metastatic sites and in endocrine pathway for breast cancer/drug resistance

ABCF3 Also present in promastigotes (one of five forms in the life cycle of trypanosomes)

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 4 of 14

Major ABC transporters involved in MDR of cancer The assembly of different ABC efflux transporters across cell membrane is similar. It is composed of transmem- brane domains (TMDs) each contains a number of membrane-spanning ?-helices (5–10 helices) and nucleotide-binding domains (NBDs). The TMD is the site where the substrate binds to the transporter, whereas NBD exerts ATPase activity that hydrolyses ATP molecules to provide the energy required for the substrate (drug) efflux process against concentration gra- dients to extracellular space (Avendaño and Menéndez 2015; Gottesman and Ling 2006; Yu et al. 2016). ABC transporters appear as full transporters or half trans- porters that dimerize to form functional full transporter units.

Three efflux transporters have been investigated in much more detail concerning their role for MDR in can- cer cells: ABCB1 (also termed P-glycoprotein, P-gp, or MDR1), ABCC1 (also termed MDR-associated protein 1 or MRP1), and ABCG2 (also termed breast cancer resist- ance protein BCRP or mitoxantrone resistance protein MXR) (Fig. 3).

ABCB1 (P-gp, MDR1) ABCB1 was the first efflux protein to be identified in MDR Chinese hamster ovary cells (CHO) by Juliano and Ling in 1976 (Juliano and Ling 1976). It is a 170 kDa glycoprotein that is expressed in liver, placenta, kidney, intestine- and blood-brain barriers, where it has detoxifi- cation and transport physiological functions. ABCB1 is

Table 1 Families of human ABC transporters and their functions. Data were adapted from Vasiliou et al. (2009) (Continued)

ABC transporter family ABC transporter Major function

ABCG ABCG1 Cholesterol transport

ABCG2 MDR, xenobiotic efflux

ABCG4 Found in macrophage, eye, brain and spleen

ABCG5 Sterol transport

ABCG8 Sterol transport

Fig. 3 Schematic presentation showing the structure of major ABC transporters involved in MDR. Adapted from (Avendaño and Menéndez 2015) under permission from Elsevier Inc

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 5 of 14

the most extensively studied efflux transporter and ac- counts for the efflux of about half the number of anti- cancer drugs used in clinic (Avendaño and Menéndez 2015). In cancer cells, the overexpression of ABCB1 con- fers MDR phenotype to cells against diverse traditional chemotherapeutic drugs of unrelated chemical structures and variable mechanisms of actions such as paclitaxel, doxorobicin, and vinblastine and many others (Loo and Clarke 2005). In addition, the ABCB1 transporter also mediates the efflux of the marine antileukemia drug imatinib (Avendaño and Menéndez 2015). The human ABCB1 protein contains 1280 amino acid

residues forming 2 similar halves. Each half contains one TMD with six ?-helices (TMD1 and TMD2) and a hydro- philic NBD (NBD1 and NBD2) (Fig. 3). The binding of ABCB1 drug substrates to the TMDs causes a subsequent hydrolysis of ATP molecule that in turn leads to a con- formational change in the shape of the transporter expel- ling the drug out of the cells (Hyde et al. 1990; Karthikeyan and Hoti 2015). This prohibits the intracellu- lar accumulation of drugs from reaching their target, and eventually making chemotherapy ineffective. Natural che- mosensitizers that proved to modulate the function of ABCB1 are listed in Tables 2 and 3.

ABCC1 (MRP1) ABCC1 is a 190 kDa ABC transporter, which is expressed in liver, bowel, and excretory organs. It is also expressed in sanctuary sites such as the blood-brain bar- rier. Although the similarity between amino acid se- quence of ABCB1 and ABCC1 is as low as 15%, the resistance conferred through both proteins is signifi- cantly overlapping (Leschziner et al. 2006). As displayed in Fig. 3, the structure of ABCC1 is composed of three TMDs (TMD0, TMD1, and TMD2) and two cytoplasmic NBDs. Several chemotherapeutic agents such as doxoro- bicin, topotecan, and vincristine are substrates of ABCC1 in cancer cells (Kathawala et al. n.d.). However, ABCC1 did not show efflux activity toward taxanes (i.e., paclitaxel as known ABCB1 substrate) (Morrow et al. 2006). Many modulators of ABCB1 such as verapamil and cyclosporine A inhibit the function of ABCC1 as well (Zhou et al. 2008). Natural chemosensitizers that modulate the function of ABCC1 are listed in Tables 1 and 2.

ABCG2 (BCRP, MXR) ABCG2 is a 72 kDa ABC half transporter and contains only one TMD and one NBD (Fig. 3) and only func- tions upon dimerization or by tetramer formation (Karthikeyan and Hoti 2015). This transporter was first identified and characterized in a MDR breast can- cer cell line (MCF7) (Doyle et al. 1998). It is expressed normally in cells membranes of small intestine,

placenta, brain, prostate, and ovaries. ABCG2 is also expressed in many types of cancer cells. Amphipathic molecules are substrates for ABCG2 transporter. This transporter also shares with other transporters the property of transporting structurally unrelated drugs. It can effectively efflux mitoxantrone and camptothe- cin as well as fluorescent dyes. Natural chemosensiti- zers that modulate the function of ABCG2 are listed in Tables 1 and 2.

Generations of chemosensitizers Extensive research work has been performed to in- hibit ABC transporter function and expression to re-sensitize cancer cells to chemotherapy. Therefore, inhibitors (chemosensitizers) block the transporter to increase drug accumulation in MDR cancer cells, which results in a better cytotoxic effect by the corre- sponding chemotherapeutic drug (Wu et al. 2011). Three distinct generations of chemosensitizers have been classified according to the relative affinity, tox- icity, and specificity (Palmeira et al. 2012).

First-generation chemosensitizers Early attempts to screen for ABC transporter inhibitors employed already available drugs that are used in the clinic such as the calcium channel blockers verapamil (Tsuruo et al. 1981), immunosuppressive drugs such as cyclosporine A (Shiraga et al. 2001), and the antimalarial drug quinine (Karthikeyan and Hoti 2015; Krishna and Mayer 2001). However, the original pharmacological ac- tivity of these first-generation drugs (chemosensitizers) caused non-desirable toxicity to non-cancerous cells, were non-specific, and had low affinity to the ABC transporter so that they required high doses to function in vivo. Examples of first-generation chemosensitizers are displayed in Fig. 4.

Second-generation chemosensitizers The limitations recorded with first-generation chemosensiti- zers led to subsequent attempts to chemically modify P-gp inhibitors and the second generation of chemosensitizers emerged. Examples are chemically modified analogues of first-generation chemosensitizers such as dexverapamil (verapamil’s R-enantiomer) and PSC833 (valspodar, modi- fied from cyclosporine A). Although second-generation chemosensitizers showed potent chemosensitization in MDR cancer cells in vitro, they displayed toxicity in ani- mal models (Abdallah et al. 2015; Nawrath and Raschack 1987; Pirker et al. 1990). Furthermore, they caused drug-drug interaction in clinical trials, since they showed cytochrome P450 inhibitory activities (Klinkhammer et al. 2009). Examples of second-gener- ation chemosensitizers are displayed in Fig. 5.

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 6 of 14

Third-generation chemosensitizers The advances in quantitative structure-activity relation- ship (QSAR) and combinatorial chemistry led to the emergence of the third-generation chemosensitizers with potent affinity to P-gp, less toxicity, and strong activity such as R1010933 (laniquidar), LY335979 (zosuquidar), GF120918 (elacridar), VX-710 (biricodar), and XR9576 (tariquidar) (Fig. 6). However, data from clinical trials re- vealed dual interactions with different types of ABC trans- porters (less selectivity to inhibit a given transporter) (Avendaño and Menéndez 2015; Toppmeyer et al. 2002; Yanagisawa et al. 1999).

Mechanism of chemosensitization of MDR cells Avendano and co-workers (2015) summarized six pos- sible mechanisms of actions of ABCB1/P-gp chemosen- sitizers (Fig. 7):

1. The chemosensitizer (e.g., verapamil) can be recognized as transporter substrate and lock the transporter in a cycle of transport and ATP hydrolysis, which in turn increases intracellular drug concentration.

2. Competitive inhibition by some chemosensitizers such as zosuquidar with longer and higher affinity to the drug binding site at the TMD of the transporter. Such compounds compete with the actual anticancer drug on the binding site of P-gp and block its transport.

3. Non-competitive inhibition of transporter by some chemosensitizers such as Cis- flupenthixol that bind important amino acid residues on P-gp sites other than the drug binding site (allosteric inhibition) and possibly interference with the conformation responsible for drug efflux.

Fig. 5 Examples of second-generation chemosensitizers

Fig. 4 Examples of first-generation chemosensitizers

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 7 of 14

Fig. 6 Examples of third-generation chemosensitizers

Fig. 7 Possible mechanisms of ABCB1/p-gp chemosensitizers. Adapted from (Avendaño and Menéndez 2015) under permission from Elsevier Inc

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 8 of 14

Table 2 Examples of natural chemosensitizers of ABC transporters isolated from plants

Targeted ABC transporter Chemosensitizer Reference

ABCB1/P-gp/MDR-1 5-Bromotetrandrine (Jin et al. 2005)

Abietane diterpene (Madureira et al. 2004a)

Alisol B 23-acetate (Wang et al. 2004a)

Amooranin (Ramachandran et al. 2003)

Baicalein and derivatives (Lee et al. 2004)

Biochanin A (Zhang and Morris 2003)

Bitter melon extract (Limtrakul et al. 2004)

Bufalin (Mahringer et al. 2010)

Cannabinoids (Zhu et al. 2006; Holland et al. 2006)

?-Carotene (Teng et al. 2016)

Catechins (Kitagawa et al. 2004)

Cepharanthine (Koizumi et al. 1995)

Coumarins (Raad et al. 2006)

Curcumin and semisynthetic derivatives (Chearwae et al. 2004; Anuchapreeda et al. 2002; Ooko et al. 2016)

Cycloartanes (Madureira et al. 2004b)

Deoxyschizandrin (Yoo et al. 2007)

Didehydrostemofolines (Umsumarng et al. 2017)

Eudesmin (Lim et al. 2007)

Euphocharacins A-L (Corea et al. 2004)

Ginkgo biloba extract (Nabekura et al. 2008; Fan et al. 2009)

Ginsenoside Rg (Kim et al. 2003)

Grapefruit juice extracts (de Castro et al. 2007)

Hapalosin (Palomo et al. 2004)

Hypericin and hyperforin (Wang et al. 2004b)

Isoquinoline alkaloid, isotetrandrine (Wang and Yang 2008)

Isostemofoline (Umsumarng et al. 2017)

Jatrophanes (Hohmann et al. 2003; Reis et al. 2016)

Kaempferia parviflora extracts (Patanasethanont et al. 2007a)

Kavalactones (Weiss et al. 2005)

Morin (Zhang and Morris 2003)

Ningalin B and derivatives (Soenen et al. 2003; Tao et al. 2004)

Opiates (Hemauer et al. 2009)

Phloretin (Zhang and Morris 2003)

Piperine (Han et al. 2008)

Polyoxypregnanes (KKW et al. 2017)

Protopanaxatriol ginsenosides (Choi et al. 2003)

Pyranocoumarins (Wu et al. 2003)

Quercetin (Limtrakul et al. 2005; Scambia et al. 1994)

Schisandrol A (Fong et al. 2007)

Sesquiterpenes (Munoz-Martinez et al. 2004)

Silymarin (Zhang and Morris 2003)

Sinensetin (Choi et al. 2002)

Stemona curtisii root extract (Limtrakul et al. 2007a)

Taxane derivatives (Brooks et al. 2004; Zhao et al. 2004)

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 9 of 14

4. Some surfactants, anesthetics, and fluidizers non- specifically perturb membrane lipids and thereby increase the rates of drug uptake (Ferte 2000; Eytan 2005).

5. Some chemosensitizers interfere with the ATP- binding domain of the transporter. An example of this mechanism is the trapping of ADP by vanadate at the ATP binding site (Urbatsch et al. 1995).

6. Some chemosensitizers can interfere with the intracellular ABCB1-mediated drug sequestration in

vesicular membrane (e.g., lysosomal sequestration (Yamagishi et al. 2013)) making the drug more available to its cellular targets.

Natural products: the fourth-generation of MDR chemosensitizers The high biodiversity, good oral bioavailability, and rela- tively low intrinsic toxicity of natural products enabled the discovery of new chemical scaffolds for drug development. Due to the limitations encountered by three generations of

Table 2 Examples of natural chemosensitizers of ABC transporters isolated from plants (Continued) Targeted ABC transporter Chemosensitizer Reference

Terpenoids (Yoshida et al. 2006)

Tetrandine (Fu et al. 2004)

Vitamin E TPGS (Collnot et al. 2007)

ABCG2/BCRP/MXR 3?-4?-7-Trimethoxyflavone (Katayama et al. 2007)

6-Prenylchrysin (Ahmed-Belkacem et al. 2005)

Acacetin (Imai et al. 2004)

Biochanin A (Zhang et al. 2004)

Cannabinoids (Holland et al. 2007)

Chrysin (Zhang et al. 2004)

Curcumin (Chearwae et al. 2006a)

Daizein (Cooray et al. 2004)

Eupatin (Henrich et al. 2006)

Genistein (Imai et al. 2004)

Ginsenosides (Jin et al. 2006)

Harmine (Ma and Wink 2010)

Hesperetin (Cooray et al. 2004)

Kaempferol (Imai et al. 2004)

Naringenin (Imai et al. 2004)

Plumbagin (Shukla et al. 2007)

Quercetin (Cooray et al. 2004)

Resveratrol (Cooray et al. 2004)

Rotenoids (Ahmed-Belkacem et al. 2007)

Silymarin (Cooray et al. 2004)

Stilbenoids (Morita et al. 2005)

Tectochrysin (Ahmed-Belkacem et al. 2005)

Terpenoids (Yoshida et al. 2008)

Tetrahydrocurcumin (Limtrakul et al. 2007b)

ABCC1/MRP1 Cannabinoids (Holland et al. 2008)

Cepharanthine (Abe et al. 1995)

Curcumin (Chearwae et al. 2006b)

Ginkgo biloba extract (Nabekura et al. 2008)

Kaempferia parviflora extracts (Patanasethanont et al. 2007b)

Myricetin (van Zanden et al. 2005)

Quercetin (Leslie et al. 2001; Wu et al. 2005)

Stemona curtisii root extract (Limtrakul et al. 2007a)

Hamed et al. Bulletin of the National Research Centre (2019) 43:8 Page 10 of 14

chemosensitizers, natural products are attractive partners for the combination with chemotherapy to enhance their cancer cytotoxic effects and reverse MDR. Edible phyto- chemicals such as curcumin, quercetin, and kaempferol block ABCB1 function and reverse MDR in human cancer cell lines (Limtrakul et al. 2005). Furthermore, some natur- ally derived compounds such as trabectedin, cytarabine, and halaven are clinically useful based on their strong che- mosensitizing properties (Huang 2007; Shi et al. 2007a; Abraham et al. 2010; Lopez and Martinez-Luis 2014). Herein, natural compounds such as phytochemicals,

marine, or fungal compounds were presented as chemo- sensitizers of MDR cancer cells (Tables 2 and 3). These natural product chemosensitizers belong to diverse chemical classes, such as flavonoids, coumarines, terpe- noids, etc. Listed natural products target the three major transporters ABCB1, ABCC1, and ABCG2.

Conclusion A major hurdle of successful cancer chemotherapy is MDR caused by ABC transporters. Extensive research has been carried out to identify chemosensitizers with high selectivity, high affinity, and low toxicity. Three generations of chemosensitizers that reverse MDR have emerged without satisfactory clinical success due to limi- tation of their toxicity, low affinity, and non-selectivity. Natural products may represent attractive alternatives to synthetic compounds for the development as chemosen- sitizers in combination with chemotherapeutic agents to enhance their efficacy in cancer cells.

Abbreviations ABC: ATP binding cassette; BCRP: Breast cancer resistance protein; MDR: Multidrug resistance; MRP: MDR-related protein; MXR: Mitoxantrone resistance protein; NBD: Nucleotide binding domain; P-gp: P-glycoprotein; TMD: Transmembrane domain

Acknowledgements The authors acknowledge Elsevier Inc. for giving the permission to re-use Figs. 1, 2, 3, and 7 from cited references.

Funding No sources of funding to be declared.

Availability of data and materials Not applicable.

Authors’ contributions All Authors have contributed in writing, reading, and approval of the final manuscript.

Ethics approval and consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests The authors declare that they have no competing interests.

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Received: 20 November 2018 Accepted: 3 January 2019

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Abraham I et al (2010) Marine sponge-derived sipholane triterpenoids reverse P- glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells. Biochem Pharmacol 80(10):1497–1506.

Ahmed-Belkacem A et al (2005) Flavonoid structure-activity studies identify 6- prenylchrysin and tectochrysin as potent and specific inhibitors of breast cancer resistance protein ABCG2. Cancer Res 65(11):4852–4860.

Ahmed-Belkacem A et al (2007) Nonprenylated rotenoids, a new class of potent breast cancer resistance protein inhibitors. J Med Chem 50(8):1933–1938.

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