Medic i n al chemis
`
`y
`
`tr
`
`ISSN: 2161-0444 Medicinal chemistry
`
`Drug Targets for Cancer Treatment: An Overview
`Shashank Kumar1, Mohammad Kaleem Ahmad1, Mohammad Waseem1 and Abhay K Pandey2*
`1Molecular and Cell Biology Laboratory, Department of Biochemistry, King Georges Medical university, Lucknow-226003, India
`2Department of Biochemistry, University of Allahabad, Allahabad-211002, India
`
`Abstract
`Cancer is one of the major cause of death worldwide. Malignant cells display metabolic changes, when compared
`to normal cells, because of both genetic and epigenetic alterations. Number of drugs being used for the cancer
`treatment follows different mechanisms of action. Therapeutic strategies include targeting of drugs at specific genes
`or proteins/enzymes found in cancer cells or the internal tissue environment which contributes to growth and survival
`of these cells. Targeted therapy is often used along with chemotherapy and other treatments to restrict the growth
`and spread of cancer cells. During the past few decades, targeted therapy has emerged as a promising approach
`for the development of selective anticancer agents. There is a class of targeted therapy drugs called angiogenesis
`inhibitors which focus on blocking the development of new blood vessels in tumor tissues. In addition, anticancer drugs
`also include DNA intercalators, DNA synthesis inhibitors, transcription regulators, enzyme inhibitors etc. This review
`focuses on major classes of anticancer drug targets and their therapeutic importance.
`
`Keywords: Anticancer drug targets; Angiogenesis; Gene regulation;
`Enzyme; Microtubules
`Introduction
`Cancer is the second leading cause of death in Europe and
`America. Tremendous resources are being invested all around the
`world for developing preventive, diagnostic, and therapeutic strategies
`for cancer [1]. Several pharmaceutical companies and government/
`non-government organizations are involved in the discovery and
`development of anticancer agents [2]. Identification of novel cytotoxic
`compounds has led to the development of anticancer therapeutics for
`several decades. Boom of knowledge in molecular sciences, genomics
`and proteomics has also helped in creating new potential drug targets.
`This has changed the paradigms of anticancer drug discovery toward
`molecularly targeted therapeutics. There are unique challenges and
`opportunities in discovery of anticancer drug delivery which might
`reflect at each stage of the drug development process [3]. Cancer is
`primarily a disease of uncontrolled cell division, thus identification
`of anti-proliferative compounds and their effects on regression of
`tumor size are the main aims for therapeutic discovery. For this
`purpose murine models of cancer were developed and several clinically
`important anticancer compounds were identified [1]. Differentiated
`result outputs among fast growing and slow growing tumors led
`investigators to modify the screening protocols to include a variety
`of cell lines and tumor types. The rationale that cancer cells are more
`likely to be replicating than normal cells makes the basis for targeting
`cell division process by most of the chemotherapeutics. Unfortunately
`significant toxicity is associated with chemotherapeutics as they lack
`specific action [1-3].
`complementary
`two
`of
`consists
`Double-helical DNA
`sugar-phosphate poly-
`strands
`running
`anti-parallel having
`deoxyribonucleotide backbone associated with specific hydrogen
`bonding between nucleotide bases [4]. In a given DNA sequence
`difference in chemical feature of the molecular surfaces in either groove
`forms the basis for molecular recognition by small molecules and
`proteins. B-form of the DNA i.e. biologically relevant double helix is
`characterized by a shallow wide major groove and a deep narrow minor
`groove [5]. DNA replication, transcription and protein synthesis are
`the major steps in cell growth and division. Being carrier of genetic
`information as well as central to tumorigenesis and pathogenesis, DNA
`is a major target for drug development. There is always a challenge for
`drug to achieve maximum specific DNA binding affinity. The other
`thing that needs consideration is that drug should not affect cellular
`
`and nuclear transport activity of the normal cells. Some of the most
`effective anticancer agents that target DNA are known to produce
`significant survival rate in cancer patients when used in combination
`with drugs having different mechanisms of action [6]. Besides DNA,
`RNA, enzymes and other proteins also contributes as major targets for
`anticancer drug development [7]. Structures of some anticancer drugs
`are depicted in Figure 1. In this review we have tried to discuss some
`molecular aspects of anticancer drug mechanisms.
`Angiogenesis Inhibitors
`Angiogenesis (AG) is the process by which tumour develops new
`blood supply (neovascularisation) for the growth and metastasis.
`Small tumours can obtain oxygen and nutrients by diffusion but
`as they become enlarged they need to develop new blood vessels
`for the fulfillment of required nutrients for growth, invasion and
`metastasis. Different anti- and pro-angiogenic factors are involved
`in the development of blood vessels in a complex equilibrium [8]. In
`physiological processes such as wound healing this equilibrium may
`go in favor of angiogenesis by inflammation or hypoxia. But on the
`other hand it may be the part of the pathological process in cancer
`or other chronic inflammatory diseases. Vascular endothelial growth
`factor (VEGF), angiogenin, transforming growth factor-β (TGF-β) and
`fibroblast growth factor (FGF) are some pro-angiogenic factors that
`are released in tumor associated angiogenesis which in turn induces
`the proliferation, migration and invasion of endothelial cells in new
`vascular structures [8]. Platelet derived growth factor receptor and cell
`adhesion molecules (e.g., integrins) play important role in the process of
`angiogenesis. Oxygen deprivation, oncogenic mutations, inflammation
`and mechanical stress are the stimulus that initiates growth of new
`vessels in tumor (angiogenic switch). This leads to vascularisation
`
`*Corresponding author: Abhay K. Pandey, Department of Biochemistry, University
`of Allahabad, Allahabad-211002, India, E-mail: akpandey23@rediffmail.com
`Received February 24, 2015; Accepted March 17, 2015; Published March 19
`2015
`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets
`for Cancer Treatment: An Overview. Med chem 5: 115-123. doi:10.4172/2161-
`0444.1000252
`Copyright: © 2015 Kumar S, et al. This is an open-access article distributed under
`the terms of the Creative Commons Attribution License, which permits unrestricted
`use, distribution, and reproduction in any medium, provided the original author and
`source are credited.
`
`Med chem
`ISSN: 2161-0444 Med chem, an open access journal
`
`Volume 5(3): 115-123 (2015) - 115
`
`Review Article
`
`Kumar et al., Med chem 2015, 5:3
`DOI: 10.4172/2161-0444.1000252
`
`Open Access
`
`Genome Ex. 1022
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`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets for Cancer Treatment: An Overview. Med chem 5: 115-123.
`doi:10.4172/2161-0444.1000252
`
`Carmustine
`
`O
`
`Cl
`
`NH
`
`N
`
`N O
`
`Cl
`
`Daunorubicin
`
`OH
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`CH3
`
`Melatonin
`
`
`CH3
`
`O
`
`O
`
`CH3
`OH
`
`CH3
`
`OH
`
`NH2
`
`NH
`
`CH3
`
`NH
`
`O
`
`Raloxifene
`
`OH
`
`S
`
`OH
`
`O
`
`N
`
`O
`
`OH
`
`N
`
`CH3
`
`O
`
`OH
`
`NH
`
`OH
`
`O
`
`Minocycline
`
`OH
`
`O
`
`OH
`
`O
`
`NH2
`
`O
`
`OH
`
`CH3
`
`H
`
`H
`
`N
`
`CH3
`CH3
`Aminopterin
`
`
`O
`
`NH2
`
`NH
`
`N N
`
`N
`
`NH2
`
`N
`
`CH3
`CH3
`
`O
`
`Deguelin
`
`
`H
`
`O
`
`H
`
`O
`
`O
`
`O
`
`CH3
`Podophyllotoxin
`
`
`OH
`
`O O
`
`O
`
`O
`
`O
`CH3
`
`O
`CH3
`
`O
`CH3
`
`CH3
`
`O
`
`Figure 1: Structure of some anticancer drugs.
`
`and expression of pro-angiogenic factors in tumor [8]. Some of the
`angiogenesis inhibitors and their mode of action are shown in Table 1.
`VEGF signaling through its receptor tyrosine kinase is the major
`inducer of angiogenesis. VEGFR-1, 2, and 3 are the three receptor
`tyrosine kinases of VEGFR family which mediate the angiogenic effect
`[9]. In endothelial cells stimulation of VEGFRs, other tyrosine kinases,
`G-proteins and serine/threonine kinases cause massive activation of
`signaling pathways. Src homology 2 (SH2) and b-cell (Shb) protein act
`as adapter molecules in VEGFR mediated signaling in angiogenesis.
`Endothelial cell migration, proliferation, and survival are the
`important processes involved in angiogenesis. These event takes place
`by the activation of PI3K (phosphatidylinositol 3-kinase) and Akt/PKB
`(serine threonine kinase/protein kinase B), by virtue of Shb protein
`
`interaction with VEGFR-2 phosphorylation site. For last three decades
`AG has been taken as an appealing target for anticancer drugs [9]. Till
`know about thirty AG inhibitors are in clinical trials and some of them
`have been approved for the treatment of malignancy. AG inhibitors
`play role as cytostatic rather than cytotoxic drugs. The anti-angiogenic
`drugs have capability to reduce the production of pro-angiogenic
`factors as well as their binding efficacy to respective receptors which
`results into their blockage of action [8,9].
`DNA Intercalators and Groove Binding Agents
`Intercalation and groove binding are the major mechanisms
`underlying drug-DNA interaction. Insertion of a planar molecule
`between DNA base pairs is known as intercalation which results
`
`Med chem
`ISSN: 2161-0444 Med chem, an open access journal
`
`Volume 5(3): 115-123 (2015) - 116
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`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets for Cancer Treatment: An Overview. Med chem 5: 115-123.
`doi:10.4172/2161-0444.1000252
`
`Name
`Angiostatin K13
`
`DLαDifluoromethylornithine
`
`Endostatin
`Fumagillin
`Genistein
`Minocycline
`Staurosporine
`(±)Thalidomide
`
`Mode of Action
`Inhibitor of endothelial cell growth and angiogenesis.
`Inhibition of ornithine decarboxylase (ODC) and blocks angiogenesis
`
`Inhibits endothelial cell proliferation; Potent inhibitor of angiogenesis and tumor growth as well.
`Inhibitor of endothelial cell proliferation and angiogenesis.
`Down regulates the transcription of genes involved in controlling angiogenesis.
`Inhibits endothelial cell proliferation and angiogenesis.
`Blocks angiogenesis by inhibition of up regulated VEGF expression in tumor cells.
`Inhibits biosynthesis of tumor necrosis factor α (TNFα); inhibits angiogenesis.
`Table 1: Angiogenesis inhibitors and their mode of action as anticancer agent.
`
`References
`[10]
`
`[11]
`
`[12]
`[13]
`[14]
`[15]
`[16]
`[17]
`
`in the reduction of lengthening and helical twist of the DNA [18].
`Approximately 4 kcal per mol free energy is used to establish the
`intercalation cavity. Some favorable contributions viz., hydrophobic,
`ionic, hydrogen bonding, and vander Waals forces are also involved
`[18]. DNA intercalating agents may be divided into mono (e.g.
`ellipticine, actinomycins and fused quinoline compounds) and bi/
`poly (e.g. ditercalinium and echinomycin) functional intercalating
`molecules. The two intercalating units (usually cationic) in bifunctional
`intercalators are separated by a spacer chain that must be long enough
`to allow double intercalation [19]. Recognition and function of DNA-
`associated proteins (polymerases,
`topoisomerases,
`transcription
`factors and DNA repair systems) are disturbed by DNA intercalating
`agents. Bi/tricyclic fused or non-fused ring structures have been
`traditionally used as DNA intercalating agents. They are known to
`be used as antimalarial, antibiotic, antitumor and antineoplastic
`agents. The intercalators may be toxic or non toxic depending on the
`presence/absence of various functional groups viz., basic, cationic,
`or electrophilic required for genotoxicity [20,21]. Groove binding
`molecules (usually crescent-shaped) unlike intercalators bind to the
`minor groove of DNA as a standard lock-and-key model and do not
`induce large conformational changes in DNA. Here, for the creation
`of binding site, cost of free energy is not required and the associations
`are stabilized by intermolecular interactions [22]. DNA intercalators
`are less sequence selective and show a preference for G-C regions. On
`the other hand groove binding molecules are more sequence selective
`and do not show G-C region preference [23]. Intercalators and groove
`binders have proven clinical utility both as anticancer and antibacterial
`agents. For example mitomycin and anthracyclines are exemplified
`both as DNA crosslinker as well as groove-binding molecules [24].
`Table 2 shows some more example of DNA intercalators used as
`anticancer agents.
`DNA Synthesis Inhibitors
`It is well established that without purines, pyrimidines, serine, and
`methionine the de novo synthesis of DNA in mammalian cells can not
`be possible. Folates belong to the family of B9 vitamins that are essential
`to mammalian cells. Folic acid is not a naturally occurring folate, it
`is composed of a pteridine ring, para-aminobenzoic acid (pABA)
`and glutamate [33]. In cells folic acid undergoes reduction process
`mediated by dihydrofolate reductase (DHFR) which ultimately leads
`to production of folate polyglutamates. These polyglutamates serve as
`one-carbon donors in de novo synthesis of purines, thymidylate, and
`polyamines [34]. The understanding of the role of folate derivatives in
`humans has led to the identification and development of antifolates
`as therapeutic agents. This idea got support from the observation of
`serum folate deficiency among patients with acute leukemia in the
`early 1940s leading to new postulation that acute leukaemia might be
`the result of folate deficiency [33]. Ribonucleotide reductase (RNR) is
`an enzyme responsible for the de novo conversion of ribonucleoside
`diphosphate (NDP) to deoxyribonucleoside diphosphate and also
`
`regulates the supply of intracellular dNTP [35]. The consequences of
`imbalance in the substrates for DNA synthesis may lead to mutagenesis
`and cell death. Thus maintenance of a balanced dNTP pool is a
`fundamental cellular function by RNR shows its importance in cell
`survival. Because of this activity differential expression of RNR is
`tightly regulated during cell cycle [36,37]. Aberrant replication forks,
`activation of S-phase checkpoint, and cell-cycle arrest are the some key
`goals that might be achieved by targeted inhibition of RNR [37]. RNR is
`expressed at relatively low level in normal cells while in cancer cells its
`expression level is very high for maintaining high dNTP pools required
`for DNA synthesis and proliferation. Using a structure and mechanism
`based approach scientist have designed and developed novel class of
`RNR inhibitors with potential clinical use. Recently COH29, an RNR
`inhibitor was discovered that showed activity in tissue culture and
`human tumor xenografts in mice [38]. S-phase arrest was observed in
`cell cultures treated with COH29 which is consistent with inhibition
`of RNR and its established role of catalyzing the rate-limiting step in
`dNTP synthesis and therefore DNA synthesis [39,40]. Novel binding
`pocket in RNR have been identified which is located on such a position
`that makes it potentially capable of multiple functional and biologically
`relevant effects. Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is
`metabolized intracellularly to 5'diphosphate (dFdCDP). It is another
`potent inhibitor of ribonucleotide reductase and a very promising
`anticancer drug [41]. Several DNA synthesis inhibitors have been
`enumerated along with their mode of action in Table 3.
`Transcription Regulators
`In all living cells transcription is required for the growth and
`survival. However, tumor cells require excess levels of transcription,
`including ribosomal RNA and mRNA transcription by RNA
`polymerase I and RNA polymerase II respectively. Mutations are
`responsible for the enhanced transcription in cancer cells. DNA
`transcription is dependent on the spatially and temporally coordinated
`interaction between transcriptional machinery and transcriptional
`regulatory components. Different transcription factors (TFs) have been
`reported to associate with cancer. Transcription deregulation can occur
`by aberrant activation, repression, temporal/spatial dyscoordination,
`structural changes including mutations, translocations, and fusion.
`Dysregulation of transcriptional and thereby post-transcriptional
`processes contributes to cancer initiation [51]. The TF nuclear factor
`(NF)-kB is a family of five reticuloendotheliosis (REL) proteins. The
`protein influences gene transcription that allows its translocation
`into the nucleus. Its inhibition sequesters the complex (NF-kB and its
`inhibitor IkBα) in the cytoplasm in an inactive conformation. Activation
`of NF-kB transcription factor may lead to IkBα degradation. NF-kB
`has been known to be active constitutively in several cancer types.
`It is associated with the regulation of cell survival, cell proliferation,
`invasion, metastasis and apoptosis inhibition. Thus inhibition of NF-
`kB transcription factor may result into retarded tumor formation [51].
`Targeting of a TF might inhibit several cancer related genes, since
`
`Med chem
`ISSN: 2161-0444 Med chem, an open access journal
`
`Volume 5(3): 115-123 (2015) - 117
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`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets for Cancer Treatment: An Overview. Med chem 5: 115-123.
`doi:10.4172/2161-0444.1000252
`
`Mode of Action
`
`References
`
`Name
`Bleomycin
`
`Carboplatin
`Carmustine
`Chlorambucil
`Cyclophosphamide (nitrogen mustard)
`cisDiammineplatinum(II)
`dichloride (Cisplatin)
`Melphalan
`Mitoxantrone
`
`Inhibits DNA synthesis; causes cleavage at specific base sequences. Induces apoptosis and inhibit angiogenesis.
`
`Forms DNA adduct and induce apoptosis.
`DNA alkylating/crosslinking agent effective against glioma and other solid tumors.
`Alkylates DNA; In leukemia cells induces apoptosis by p53dependent mechanism.
`Crosslinks DNA and causes strand breakage.
`
`Induces apoptosis by forming cytotoxic adducts with the DNA dinucleotide d(pGpG).
`
`Forms DNA intrastrand crosslinks by alkylation of 5'(GGC) sequences.
`Inhibits DNA synthesis by intercalating DNA.
`Table 2: DNA intercalators/groove binding agents and their mode of action as anticancer agent.
`
`[25]
`
`[26]
`[27]
`[28]
`[29]
`
`[30]
`
`[31]
`[32]
`
`References
`
`[42]
`
`[43]
`
`[44]
`
`[45]
`
`[46]
`
`[47]
`
`[48]
`
`[49]
`
`[50]
`
`Blocks thymidine biosynthesis via inhibition of dihydrofolate reductase (folic acid antagonist)
`
`Hypoxia activated antineoplastic agent
`
`Mode of Action
`
`Name
`(±)Amethopterin
`(Methotrexate)
`3Amino1,2,4benzotriazine
`1,4dioxide
`Mechanism same as methotrexate but more potent.
`Aminopterin
`Cytosine- β D-arabinofuranoside Selective inhibitor of DNA synthesis.
`5-Fluoro5' deoxyuridine
`
`Inhibits proliferation of cancer cells transformed by HRas or Trk oncogenes
`
`5-Fluorouracil
`
`Ganciclovir
`
`Hydroxyurea
`
`Mitomycin C
`
`Depletes dTTP and inhibits thymidylate synthetase; it forms nucleotides that can be incorporated into RNA and
`DNA and induces p53dependent apoptosis
`In suicide gene therapy of solid tumors, the gene for Herpes
`simplex virus thymidine kinase is delivered to tumor cells and expressed, which in turn activates ganciclovir
`cytotoxicity.
`Blocks the synthesis of deoxynucleotides by inactivating ribonucleoside reductase resulting into inhibition of DNA
`synthesis and induction cell death.
`Inhibits DNA synthesis, nuclear division, and proliferation of cancer cells.
`Table 3: DNA synthesis inhibitors and their mode of action as anticancer agent.
`
`it regulates different downstream target genes. In cancer therapy,
`the drugs that targets TFs are less known than inhibitor molecules
`targeting the signal transduction. Recently novel immunotherapies
`have been documented against some transcription factors. For example
`transcription factor WT-1 and PML-RARα are the targets for the
`treatment of leukemia and acute promyelocytic leukemia respectively
`[52,53]. Drugs that potentially target the transcription machinery
`include cyclin-dependent kinases (CDKs), RNA polymerases or
`components of associated transcriptional complexes. Inhibitor such
`as triptolide, that targets the general transcription factors TFIIH and
`JQ1 to inhibit BRD4 are administered to target the high proliferative
`rate of cancer cells [54]. Tumor suppressor genes or oncogene
`antagonists have been used as an attempt at cancer therapy targeting
`TFs. It is reported that ETS transcription factors, especially Ets-1 have
`capability to inhibit cell growth, metastasis and tumor angiogenesis.
`But no reports are available regarding trials of gene therapies targeting
`ETS transcription factors. Considering that TFs that regulate growth,
`apoptosis, angiogenesis, invasion and metastasis related genes in tumor
`cells could be molecular targets for cancer gene therapy [54]. Some
`examples of transcription regulators are shown in Table 4.
`Enzyme Inhibitors
`In contrast to normal cells, the metabolic properties of cancer cells
`are different and they depend on aerobic glycolysis for their energy
`requirement. In addition they have dysregulated fatty acid synthesis,
`Warburg-like glucose metabolism and glutaminolysis. Studies have
`shown that several enzymes in metabolic pathways act as anticancer
`targets and their inhibition is responsible for mediating apoptotic death
`in cancer cells. Hence inclusion of inhibitors of metabolic enzymes
`(e.g. glucose transporters, fatty acid synthase, hexokinase, lactate
`dehydrogenase A, pyruvate kinase M2, pyruvate dehydrogenase kinase
`
`and glutaminase etc.) in cancer therapy regimen are also important
`to enhance the efficacy of chemo/radiotherapy [60]. Estrogens and its
`receptors (ERs) are known to play important role in the progression
`and development of breast cancer [61-62]. Estrogens influence breast
`cancer through the ERα pathway, increases genetic mutations, and/or
`effects on DNA repair pathway [63,64]. Biosynthesis of estrogens from
`androgens involves a cytochrome P450 enzyme known as aromatase,
`encoded by the aromatase gene CYP19. Its expression is regulated by
`tissue-specific promoters [65]. It has been found in all the tissues in
`body including breast, brain, skin bone and muscles. It is found that
`the expression of aromatase is increased many folds in breast cancer
`tissues. Inhibition of this enzyme has been shown to be responsible
`for the decreased level of estrogen. Thus in the progression and
`development of hormone responsive breast cancers aromatase enzyme
`may have significant effects and their inhibitors (AI) can be utilized as
`chemopreventive agent [66]. AIs can be divided into steroidal (Type I
`inhibitors) or nonsteroidal (Type II inhibitors). Type I inhibitors binds
`covalently while type II binds reversibly to the aromatase enzyme.
`Amino glutethimide (Ist generation); formestane and vorozole (IInd
`generation); anastrozole, letrozole, and exemestane (IIIrd generation)
`are some examples of AIs. Testolactone, a first generation AI and is
`approved for treatment of advanced breast cancer in the United
`States [67]. Due to the development of resistance to AIs there is need
`to develop new aromatase inhibitors that could offer less severe side-
`effects and increased clinical efficacy. Unwinding and rewinding of the
`DNA helix during various processes such as replication, repair, and
`chromatin remodeling, entanglement of DNA occurs. The enzyme
`DNA topoisomerases a nature's tool solve the problem by performing
`topological transformations in DNA. They form a covalent adduct
`with DNA resulting into a transient DNA break through which strand
`passage can occur. The two types of topoisomerases i.e., type I and type
`II enzymes involves a nucleophilic attack of a DNA phosphodiester
`
`Med chem
`ISSN: 2161-0444 Med chem, an open access journal
`
`Volume 5(3): 115-123 (2015) - 118
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`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets for Cancer Treatment: An Overview. Med chem 5: 115-123.
`doi:10.4172/2161-0444.1000252
`
`Name
`
`Actinomycin D
`
`Mode of Action
`Inhibits cell proliferation by forming complex with DNA and blocks production of mRNA (RNA polymerase inhibition); Induces
`apoptosis.
`Complexes to DNA and blocks production of mRNA by RNA polymerase.
`Daunorubicin
`Inhibits reverse transcriptase and RNA polymerase by binding to DNA.
`Doxorubicin
`Homoharringtonine Binds to the 80S ribosome in eukaryotic cells and inhibits protein synthesis by interfering with chain elongation.
`Idarubicin
`Antileukemia agent with higher DNA binding capacity and greater cytotoxicity than daunorubicin
`Table 4: Transcription regulators and their mode of action as anticancer agent.
`
`Name
`
`S(+)Camptothecin
`
`Curcumin
`Deguelin
`
`Etoposide
`
`Formestane
`Fostriecin
`
`Hispidin
`
`2Imino1imidazolidineacetic
`Acid (Cyclocreatine)
`
`Mevinolin
`
`Trichostatin A
`
`Mode of Action
`Binds irreversibly to the DNA topoisomerase I complex leading to the irreversible cleavage of DNA and the destruction
`of cellular topoisomerase I by the ubiquitin proteasome pathway. Induces apoptosis in many normal and tumor cell lines
`Potent inhibitor of protein kinase C, EGFR tyrosine kinase and IκB kinase. Induces apoptosis in cancer cells.
`Inhibitor of activated Akt. Does not affect MAPK, ERK1/2 or JNK.
`Binds to the DNA topoisomerase II complex to enhance cleavage and inhibit religation; inhibits synthesis of the oncoprotein
`Mdm2 and induces apoptosis in tumor lines that over express Mdm2.
`Aromatase inhibitor
`Interferes with the reversible phosphorylation of proteins that are critical for progression through the cell cycle.
`Potent inhibitor of protein kinase Cβ.
`Creatine analog; decreases the rate of ATP production via
`creatine kinase and reduces the proliferation of tumor cell lines characterized by high levels of creatine kinase
`expression.
`Inhibits mevalonic acid production and induces apoptosis in numerous cancer cell lines, perhaps, in part, by inhibiting
`the isoprenylation of Rhofamily GTPases.
`Histone deacetylase inhibitor that enhances the cytotoxic efficacy of anticancer drugs that target DNA.
`Table 5: Enzyme modulators and their mode of action as anticancer agent.
`
`References
`
`[55]
`
`[56]
`[57]
`[58]
`[59]
`
`References
`
`[72]
`
`[73]
`[74]
`
`[75]
`
`[76]
`[77]
`[78]
`
`[79]
`
`[80]
`
`[81]
`
`bond by a tyrosyl residue [68]. Type I enzyme is composed of
`N-terminal, core,
`linker and the C-terminal domains [69-71].
`Different natural and synthetic molecules are known to target DNA
`topoisomerases represents the important class of antitumor drugs. The
`transesterification reaction involved in cleavage and relegation of DNA
`backbone is exploited by cytotoxic agents. Table 5 shows example of
`some enzyme modulators used as anticancer agents.
`Gene Regulation
`Epigenetic alterations in DNA are potentially reversible and
`hence are involved in the earliest steps of malignant transformation.
`Interventions using epigenetically active compounds are considered as
`promising targets for anti-cancer therapy [82,83]. Beside these a number
`of challenges remain prior to any epigenetic intervention against cancer.
`Massive deregulation of the epigenetic machinery including DNA
`methylation, histone modifications and non-coding RNAs contributes
`to all major cancer hallmarks [84]. In eukaryotic cells acetylation and
`deacetylation of histones is an important event for transcriptional
`regulation for which histone acetyltransferase (HATs) and histone
`deacetylases (HDACs) are responsible, respectively [85]. Acetylation
`to lysine group of chromatin produces relaxation which intern allows
`increased transcription of the gene. On the other hand deacetylation
`increases condensation of chromatin thereby decreasing the rate of
`transcription of particular part of the chromatin [86,87]. It is found
`that HDACs are over expressed in tumors and this inhibits expressions
`of tumor suppressor genes. Thus HDACs inhibition may be considered
`as a potential strategy for cancer treatment. Vorinostat and romidepsin
`are the two HDAC inhibitors that have been approved by the FDA
`(US Food and Drug Administration) as anticancer therapeutic [88,89].
`Metal-binding compounds such as clioquinol (a zinc ionophore) are
`increasingly believed to be an important group of anticancer agents. It
`has been reported that clioquinol induces apoptosis by the inhibition
`of NF-κB signaling pathway in human cancer cells [90]. Clioquinol
`targets cyclin D1 gene at both transcriptional and post-transcriptional
`regulation level in cancer cells. It is believed that clioquinol promotes
`mRNA degradation of the cyclin D1 gene regulated by miR-302C. This
`
`implies that metal-binding compounds might affect gene expression
`at different regulatory levels. Out of which the post-transcriptional
`gene regulation may be a potential target for chemotherapy [91].
`P-glycoprotein (P-gp) is a transmembrane permeability glycoprotein
`and member of ABC super family (ATP binding cassette). It functions
`as a carrier mediated primary active efflux transporter and widely
`distributed throughout the body. P-gp is encoded by MDR1/ABCB1
`gene and was firstly identified in human cancer cells. It was found to
`be present in pancreas, elementary canal, kidney, capillary endothelial
`cells of blood brain barrier and in various other tissues like lungs, heart,
`adrenals, spleen and skeletal muscle [92]. The optimal P-gp expression
`is always required for its protective function as its over expression
`leads to multi drug resistance while toxic reactions occurs because
`of its low expression level [93]. In various cancers a correlation was
`found between increased P-gp expression and MDR1 gene mRNA
`transcription which shows its connection to MDR in cancer. A few
`novel antitumor drugs which are able to suppress P-gp expression are
`under development. Lanthanum, a new anticancer compound have
`been reported to block P-gp expres sion especially in MDR cancerous
`cells [94]. Gefitinib another compound is a selective tyrosine kinase
`inhibitor has capability to inhibited P-gp function and has been used in
`the treatment of lung cancer [95]. Some of the gene regulator and their
`targets are shown in Table 6.
`Microtubule Inhibitors
`Microtubules a component of cytoskeleton is composed of α and β
`tubulin. This heterodimer is involved in many biological process viz.,
`cell signaling, cytokinesis, intracellular transport, maintenance of cell
`shape, and polarity [104]. Due to their role in mitosis they become
`an important target for anticancer drug development. In eukaryotes
`during cell division mitotic spindle is responsible for the movement of
`chromosomes to the opposite sides of the cell. These mitotic spindles
`are nothing but are composed of microtubules having tubulin as its
`monomer [105-107]. Molecules that interfere with microtubule
`assembly are known as microtubule inhibiting agents. Currently
`these agents are used in clinical therapy as they are able to suppress
`
`Med chem
`ISSN: 2161-0444 Med chem, an open access journal
`
`Volume 5(3): 115-123 (2015) - 119
`
`Genome Ex. 1022
`Page 5 of 9
`
`

`

`Citation: Kumar S, Ahmad MK, Waseem M, Pandey AK (2015) Drug Targets for Cancer Treatment: An Overview. Med chem 5: 115-123.
`doi:10.4172/2161-0444.1000252
`
`Mode of Action
`Name
`5-Aza2' -deoxycytidine Causes DNA demethylation or hemidemethylation, creating openings that allow transcription factors to bind to DNA and
`reactivate tumor suppressor genes.
`Cholecalciferol
`Antiproliferative action on breast, prostate, and colon cancer cells
`(Vitamin D3)
`4-Hydroxytamoxifen Metabolite of tamoxifen that is a potent selective estrogen response modifier (SERM); the trans (Z) isomer has efficacy
`against estrogen sensitive cancers. The cis (E) isomer is an estrogen agonist.
`Enhances apoptotic death of cancer cells; inhibits proliferation/metastasis of breast cancer cells by inhibiting estrogen
`receptor action.
`Progesterone receptor antagonist; stimulates prolactin secretion. Pgp inhibitor.
`Selective estrogen response modifier (SERM), may have efficacy against estrogensensitive cancers.
`Selective estrogen response modifier (SERM), used therapeutically and prophylactically against estrogen sensitive tumors.
`Antitumor agent; PPARγ agonist; induces apoptosis via a p53 pathway.
`Table 6: Gene regulators and their mode of action as anticancer agent.
`
`Mifepristone
`Raloxifene
`Tamoxifen
`Troglitazone
`
`Melatonin
`
`References
`
`[96]
`
`[97]
`
`[98]
`
`[99]
`
`[100]
`[101]
`[102]
`[103]
`
`References
`
`[113]
`
`[114]
`
`[115]
`
`[116]
`[117]
`
`[118]
`
`[119]
`
`[119]
`
`Name
`
`Colchicine
`
`Nocodazole
`
`Mode of Action
`Antimitotic agent that disrupts microtubules by binding to tubulin and preventing its polymerization; induces apoptosis in several
`