Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site. Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes.

1. Targetting cancer with Ru(III/II)-phosphodiesterase inhibitor adducts: A novel
approach in the treatment of cancer
Raj Kumar Koiri ⇑
, Aditi Mehrotra, Surendra Kumar Trigun
Biochemistry and Molecular Biology Lab, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
a r t i c l e i n f o
Article history:
Received 3 November 2012
Accepted 17 March 2013
a b s t r a c t
Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anti-
cancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during
recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This
is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher
concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin com-
plexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell
specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evi-
dences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophos-
phate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor
cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator
and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facil-
itate delivery of the drugs/compounds to the tumor site.
Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant
strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged
entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such
adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, result-
ing into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to
administration of such complexes.
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
Since the discovery of anticancer properties of cisplatin (cisdi-
amminedichloro-platinum(II)) by Rosenberg in 1960s [1], the use
of metal-based complexes invited special attention in the area of
chemotherapeutics [2]. This resulted in the development of plati-
num-based anticancer agents which could respond against a wide
range of tumors like, ovarian, testicular, bladder and lung cancers
[3]. These complexes bind to N-7 of guanine and adenine bases
of DNA and thereby, they produce intrastrand/interstrand DNA
cross-links [4]. As a result, it disrupts DNA replication and genetic
information flow in the tumor cells [5]. Moreover, platinum based
complexes were found to produce a number of serious side effects
mainly due to lack of specificity for the tumor cells and attacking
DNA which is now considered as an unselective target [6]. Addi-
tionally, clinical utility of this drug is often limited due to the onset
of resistance acquired against these complexes by the tumor cells
[7,8]. This could be the reason why out of over 3000 platinum com-
pounds synthesized [9], only three; cisplatin, carboplatin and oxa-
liplatin, came in routine clinical use [10–12].
Moreover, these limitations necessitated the development of
non-platinum compounds as alternate anticancer drugs. The anti-
cancer properties of the other transition metal drugs examined in-
cluded complexes based on ruthenium, arsenic, gallium, titanium,
copper, iron, rhodium, and tin [13–18]. However, till recent, only
ruthenium complexes could derive much attention as a relevant
alternative to the platinum based drugs [19,20].
Anticancer Ru-complexes
NAMI-A,[imH][trans-RuIIICl4(dmso-S)(im)] (im = imidazole),is the
first non platinum and first Ru complex that has successfully com-
pleted phase I clinical trials as an anti-cancer agent and is currently
in phase II clinical trials. Another Ru(III) drug, KP1019, indazolium
[trans-tetrachlorobis(1H-indazole)-ruthenate(III)]2 have also success-
0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mehy.2013.03.029
Abbreviations: cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine
monophosphate; LDH, lactate dehydrogenase; PDE, cyclic nucleotide phosphodies-
terases; PDEi, cyclic nucleotide phosphodiesterases inhibitors; Ru, ruthenium; NO,
nitric oxide.
⇑ Corresponding author. Tel.: +91 9453061011.
E-mail addresses: rajkumarfrombhu@yahoo.com (R.K. Koiri), sktrigun@sify.com
(S.K. Trigun).
Medical Hypotheses 80 (2013) 841–846
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

2. fully completed phase I clinical trials [19,20]. Both these complexes
exhibited low level general toxicity, but with strong antimetastatic
activities [20,21]. We have also described that a ruthenium(II) com-
plex; Ru(II)-CNEB, could induce apoptosis in the DL (Dalton’s lym-
phoma) cells in vivo via inhibiting lactate dehydrogenase, the
enzyme which is known to be up regulated during tumor growth,
and was found toshownegligibletoxicitytothenormaltissues[22,23].
What is specific about ruthenium complexes as anticancer
agents?
Ruthenium (Ru) based complexes exhibit a number of proper-
ties that advocate them as a physiologically better acceptable com-
pounds when administered to the tumor bearing subjects. The
most important one is that they exhibit multiple accessible oxida-
tion states mimicking iron [20,24], which enables them to bind
with the circulating transferrin [25,26]. It has been reported that
as tumor cells need higher amount of iron, they express high
amount of transferrin receptor [25,26]. This provides main mecha-
nism for much of circulating Ru-complexes to preferentially accu-
mulate in the tumor cells. Such a mechanism could be accountable
for minimum Ru-toxicity to the normal tissues when administered
to the tumor bearing animals [22]. Additionally, affinity of Ru-com-
plexes for the serum albumin [27] could also attribute for their
minimum systemic toxicity and effective biodistribution.
Higher coordination number of ruthenium, compared to the
platinum, provides additional sites for fine-tuning the ligand ex-
change and thereby, allowing modulation of therapeutic properties
of these complexes [24]. Also, metal Ru-centers, being positively
charged, can bind to the negatively charged biomolecules; like pro-
teins and nucleic acids and thereby, they are likely to modulate di-
verse cellular functions [21,23]. For example, protein binding
properties of Ru-complexes have been shown to facilitate their dis-
tribution and to modulate their pharmacokinetics & mechanism of
action in a significant way [22,28].
Modulation of molecular targets by Ru-complexes
Following the pattern of cisplatin action, structural distortions
of DNA were initially speculated to be the main mechanism of anti-
cancer activities of many ruthenium and other transition metal
complexes [29]. Indeed some of them were shown to interact with
DNA/G-quadruplex [30] and could damage DNA in the tumor cells
[31]. Moreover, DNA is considered as unselective target. Recent ad-
vances in bioanalytical techniques, with high sensitivity and selec-
tivity, have revealed that other than DNA, metal-based drugs can
undergo a wide range of biomolecular interactions and therefore,
they have generated interest in proteins as relevant target for
metallodrugs [32]. Obviously, one can speculate that formulation
of ruthenium complexes targeted to proteins of critical cell func-
tions would be a better strategy to ascertain therapeutic potential
of the ruthenium-complexes [28,33].
There are reports to suggest that some ruthenium complexes
could modulate specific biochemical properties like, production
of ROS [34], inhibition of survival kinases [35] & redox reactions
in the cancer cells [36]. A Ru(III) complex was found to inhibit
DNA replication and RNA synthesis in vivo [24]. NAMI-A could pro-
duce cytotoxicity by interacting with DNA and by inhibiting type
IV collagenase activity as well [24].
Targeting non-DNA molecules: a better option for anticancer
agents
Based on the recent advances in the area of cancer genomics, as
compared to the DNA-adduct formation guided design of
metallodrugs, it is now being argued to target non-nuclear mecha-
nisms which are over activated in the cancer cells [37]. One of the
most plausible cancer associated phenomena is the switching over
to glycolytic phenotype acquired by most of the tumors to meet
their extra energy need [38]. As our understanding of molecular
biology and cell signaling becomes clearer, key molecular targets
of this pathway are being identified as relevant pharmacological
targets by many workers including evaluation of certain Ru(II)-
complexes from our lab also [22,39].
Structural diversity makes Ru-complexes a better choice
The multimodal actions of Ru-complexes were attributed to
their structural diversity generated due to different ligands at-
tached to the ruthenium metal center. As a result, many of them
could enhance their water solubility, stability, cellular specificity
and could also overcome with the problem of drug resistance
[28,33,40,41]. Some important ligands being tried have been
amines, imines, DMSO & polypyridyl arene compounds
[24,25,41]. Amongst these, imidazole ligand containing NAMI-A
system and water-soluble arene ruthenium complexes have
emerged as important molecules to design anticancer drugs with
low toxicity and high tumor specificity due to their greater affinity
for the cancer cells [25,28,41]. Taking together, it is evident that
coupling of Ru-complexes with molecules of distinct cellular tar-
gets could be one of the promising strategies for developing syner-
gistic anticancer drugs [33,41].
Ru(II) vs. Ru(III)
As compared to Ru(III), Ru(II) complexes could be more effective
for tumor cell toxicity [40]. This is because Ru(II) complexes have
been found to bind more effectively with macromolecules and
can induce better cytotoxicity [37]. Indeed a number of Ru(II)-com-
pounds with flavonoids based ligands have been reported to en-
hance their affinity towards bio-molecules [42,43] and to
provoke better anticancer properties [22,43]. Nonetheless, in vivo
tumor cells run with relatively low electro-chemical potential
due to the low oxygen content and low pH which can reduce Ru(III)
to Ru(II) for their better cytotoxicity [37]. NMR studies have re-
vealed that the Ru(III) centers in KP1019 [44] and NAMI-A [37] un-
dergo reduction in the presence of reducing agents, like ascorbic
acid and glutathione found in the cells [40]. Thus both, Ru(II) and
Ru(III), could be exploited to formulate effective anticancer agents.
Cyclic nucleotide phosphodiesterases (PDE) and the tumor
growth
Modulation of cyclic nucleotide phosphodiesterases (PDEs) are
one of the recent and evolving inclusions in the series of biochem-
ical adaptations reported in the cancerous cells. PDEs catalyze
hydrolytic cleavage of the 30
-phosphodiester bond in the cyclic
adenosine monophosphate (cAMP) and cyclic guanosine mono-
phosphate (cGMP), converting them into AMP & GMP respectively
[45]. cAMP & cGMP are termed as second messengers involved in
maintaining bioenergetic homeostasis by relaying signals from
receptors on the cell surface to the target molecules inside the cell
[46]. Importantly, deregulation of cGMP production and unusual
activation of cAMP-controlled genes have been described associ-
ated with the tumor growth [47]. The former is linked to the
over-expression of PDE isoforms in many tumors resulting into re-
duced cGMP level [47]. During cancer progression, such changes
are likely to interfere with drug delivery also.
Interestingly, it is now evident that these tumor associated
events can be reversed using selective PDE inhibitors (PDEis)
842 R.K. Koiri et al. / Medical Hypotheses 80 (2013) 841–846

3. [47–50]. PDEi block PDE activity, resulting into passive accumula-
tion of the intracellular cGMP (Fig. 1) which in many tumor cells
has been found to induce apoptosis and cell cycle arrest [47]. Fur-
thermore, in some cases, PDEis have been demonstrated to down
regulate expression of the multi-drug resistance protein, MRP5
also [51]. This evolving mechanism is further highlighted by the
fact that the mechanism of some anticancer drugs also involves
raising of cGMP level via NO mediated activation of guanylyl cy-
clase [46]. Roles of other molecular partners to accomplish this
process have been summarized in Fig. 2. The intracellular targets
of cGMP signaling include cGMP dependent protein kinases
(PKG) & cGMP gated ion channels. When activated, they initiate
protein phosphorylation cascades leading into dilation of the blood
vessels [52]. The signal is terminated by metabolic degradation of
cGMP by PDE [46] or by ATP dependent export of cGMP from the
cell by MRP5 [51].
PDEis also up regulate the phosphoinositol-3-phosphate kinase
(PI3K)/AKT pathway and increases VEGF level to facilitate angio-
genesis in the tumors [53,54]. Employing this strategy, some PDEis
are already in clinical use. One of the most common is Sildenafil
(Viagra) which specifically inhibits cGMP-specific PDE type 5 and
in doing so, it enhances the vasodilatory effects of cGMP in the cor-
pus cavernosum, overcoming erectile dysfunciton. The same drug
is also being investigated as a cardioprotective treatment for pa-
tients with Duchenne muscular dystrophy [55]. Thus, it may be ar-
gued that PDE inhibitors can potentially improve drug delivery due
to cGMP led increased vasodilation in the growing tumors.
Use of PDEi as anticancer agents
cGMP levels are significantly reduced in the tumor cells as com-
pared with their normal counterparts [56]. Accordingly, increased
intracellular cGMP elicited by various guanylyl cyclase agonists
[57], atrial natriuretic peptide [58], YC-1 [56], nitric oxide donors
[59], and/or PDE5-selective inhibitors, for example, sildenafil and
vardenafil have been reported to induce apoptosis and inhibit cell
proliferation [47]. One of the PDE5 inhibitors has been reported to
inhibit growth of the breast cancer cells by inhibiting cGMP hydro-
lysis and activating PKG signaling to induce apoptosis in those can-
cer cells [49]. Added to this, Zhu et al. [48] have demonstrated
suppression of PDE5 gene expression by antisense pZeoSV2/ASP5
plasmid transfection resulting into a sustained increase in the
intracellular cGMP led growth inhibition and apoptosis in the hu-
man colon tumor HT29 cells. Recently, a phosphodiesterase 5
inhibitor, vardenafil, has been shown to synergize the effect of
EGCG inducing cancer cell death [54].
Furthermore, PDE5 inhibitors have been reported to serve as
chemo-sensitizers. The ABC transporters (such as ABCB1, ABCC4,
ABCC5, ABCC10 and ABCG2), whose over expression is associated
with multi-drug resistance (MDR) in cancer cells, were also found
to be the targets of PDE5 inhibitors and thereby enhancing the ac-
tion of various antineoplastic drugs [51,60–62]. Importantly, most
of these PDE5 inhibitors have shown acceptable tolerability pro-
files in the patients [62].
Presentation of the hypothesis
Review of the recent findings, as described in this article, sug-
gests that both; Ru-complexes and PDEis, adopt specific mecha-
nisms for their preferential accumulation in the tumor cells and
that both of them exhibit antitumor activities by interfering with
tumor growth associated biochemical events. Additionally, Ru-me-
tal center [Ru(II)/Ru(III)] can bind/accommodate a variety of li-
gands and thereby, it provides greater versatility for designing
potent anticancer agents with high tumor specificity. On the other
hand, PDEis are known to enhance blood supply to the target tissue
and thereby they can enhance relatively preferential drug targeting
to the tumor site. Added to this, PDEis have recently been
Soluble guanylyl cyclase
GTPcGMP5’-cGMP
PDE inhibitor
X
cGKcGK
(inactive)(active)
Protein phosphorylation
Cellularresponse
Guanylyl cyclase
receptor
Agonist
NONO donors
NO synthase
Fig. 1. NO production via NOS/NO donors activate soluble guanylyl cyclase to form cGMP from GTP. Phosphodiesterases degrade cGMP by hydrolytic cleavage of the 30
-
phosphodiester bond to form inactive 50
-GMP. Inhibitors of PDE block this activity, resulting into accumulation of cGMP, which in turn can affect the activities of cyclic
nucleotide-dependent protein kinases (cGK), leading into disturbance of constitutive cellular homeostasis of the target cells.
R.K. Koiri et al. / Medical Hypotheses 80 (2013) 841–846 843

4. described to exhibit anti-cancer activity at their own by modulat-
ing an important cell signaling cascade associated with the tumor
growth.
Therefore, it is reasonable to hypothesize a strategy involving
tagging of PDEis with the Ru-metal center to produce a Ru-PDEi
adduct which is speculated to:
(1) Increase Ru-led preferential delivery of the adduct at tumor
site.
(2) Facilitate further PDEi mediated greater perfusion of the
tumor cells and thereby preferential delivery of most of
the successively administered Ru-PDEis adduct to the
tumors in vivo.
(3) Provide double edge molecular mechanisms of Ru- & PDEis
to execute more effectively their antitumor activities to
induce apoptosis in the tumor cells with a little chance to
affect normal tissues adversely.
(4) Overcome with the problem of drug resistance.
The Experimental plan hypothesized
The following experiments may be proposed to accomplish the
hypothesis:
(A) Synthesis of Ru(III/II) complexes containing known PDE
inhibitors (e.g., inhibitors of PDE5) as ligands, for example,
sildenafil, tadalafil, zaprinast, vardenafil, DA-8159, cilosta-
mide, milrinone, trequinsin, cilastazol, OPC-33540, etc.
(B) In vitro assay of Ru(III/II)-phosphodiesterase inhibitor com-
plexes for their ability to inhibit the PDE5 activity and to
increase the level of cGMP in the cells in culture.
(C) In vivo assay of general cytotoxicity and delivery of adduct to
the tumor site.
(D) Assay of whether adduct is able to inhibit PDE5 leading into
increased level of cGMP in the tumor cells in vivo.
(E) Studies on modulation of biochemical targets like, bioener-
getic enzymes, NOS activity and antioxidant enzymes in
the tumor cells in vivo.
(F) Asssay of drug resistance proteins like BCRP, MDR1 & MRP1
in the tumor cells from Ru-PDEi adduct treated cancerous
animals.
Summary & perspective
Modulation of tumor cell biochemistry by Ru-complexes result-
ing into tumor apoptosis and PDEis mediated cell cycle arrest & tu-
mor regression are the evolving mechanisms in cancer
RuPDE inhibitor
PKC ERK
iNOS / eNOS
NO
Guanylyl cyclase
GTPcGMP5’-cGMP
RuPDE inhibitor
X
ATP
MRP5
X
ATP ADP
PKG
Downstream effectors
CREB VEGFPI3K/AKT
Lowering Ca2+ Ca2+
VSM relaxation
vasodilation
Angiogenesis blood flow in hypoxic core Accumulation of Ru(III/II) in tumor cell
Regression of cancer Apoptosis
Fig. 2. Proposed hypothesis for the mechanism of action of Ru(III/II)-PDEis adduct as an anticancer agent. This adduct is likely to inhibit metabolic degradation of cGMP by
PDE and thereby it can allow passive accumulation of cGMP. This in turn can activate cGMP dependent protein kinase (PKG) signaling in the tumor cells to enhance
vasodilation and to evoke cell cycle arrest and apoptosis. The vasodilation function, once initiated by such adducts, is likely to allow more amount of adduct to be delivered
preferentially at the tumor site. PDEis can also up regulate the phosphoinositol-3-phosphate kinase (PI3K)/AKT pathway and increases VEGF levels and thus, leading into
increased angiogenesis in the hypoxic tumor mass. This will further facilitate efficient delivery of adduct at the hypoxic core allowing effective antitumor activities of both,
the Ru-complex and the PDEis. BF – blood flow; cGMP – cyclic GMP; CREB – cAMP response element binding protein; ERK – extracellular regulated kinase; GC – guanylyl
cyclase; iNOS or eNOS – inducible or endothelial nitric oxide synthase; NO – nitric oxide; PI3K – phosphotidyl inositol-3 kinase; PKC – protein kinase C; PKG – protein kinase
G; Ru-PDEi – ruthenium phosphodiesterase inhibitor; VSM – vascular smooth muscle.
844 R.K. Koiri et al. / Medical Hypotheses 80 (2013) 841–846

5. chemotherapy. The findings from the present hypothesis will lead
to the identification of Ru-PDEis adducts effective against a num-
ber of common cancers with little normal tissue toxicity. The find-
ings on whether they are able to modulate multidrug resistance
proteins in the in vivo tumors will provide additional properties
of such complexes. Taking together, the proposed hypothesis is a
novel approach of combining antitumor properties of more than
one compounds leading into synthesis of a physiologically better
acceptable but more potent anticancer complexes, showing in-
creased tumor specificity, decreased drug resistance and multiple
cellular targets to ultimately induce apoptosis in the tumor cells.
Conflict of interest
The authors declare no conflict of interest with respect to this
article.
Acknowledgments
This work had a genesis from a Department of Biotechnology
(DBT), Govt. of India project (No. BT/PR5910/BRB/10/406/2005)
and results from a CSIR SRF to RKK. AM thanks ICMR, Govt. India
for awarding Senior Research Fellowship. The facilities provided
due to UGC-CAS and DST-FIST programmes to Department of Zool-
ogy, BHU, are also acknowledged.
References
[1] Rosenberg B, Van Camp L, Trosko JE, Mansour VH. Platinum compounds: a new
class of potent antitumour agents. Nature 1969;222:385–6.
[2] Hartinger CG, Dyson PJ. Bioorganometallic chemistry – from teaching
paradigms to medicinal applications. Chem Soc Rev 2009;38:391–401.
[3] Florea A, Büsselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of
activity, drug resistance and induced side effects. Cancers 2011;3:1351–71.
[4] Fichtinger-Schepman AM, Dijt FJ, De Jong WH, Van Oosterom AT, Brends F. In
vivo cisplatin-DNA adducts formation and removals as measured with
immunochemical techniques. In: Nicolini M, editor. Platinum and other
metal coordination compounds in cancer chemotherapy. Boston: Martinum
Nijhoff; 1988. p. 32–46.
[5] Szymkowski DE, Yarema K, Essigmann JM, Lippard SJ, Wood RD. An intrastrand
d(GpG) platinum crosslink in duplex M13 DNA is refractory to repair by
human cell extracts. Proc Natl Acad Sci USA 1992;89:10772–6.
[6] Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin
Pharmacother 2003;4:889–901.
[7] Brabec V, Kaspasrkova J. Modifications of DNA by platinum complexes.
Relation to resistance of tumors to platinum antitumor drugs. Drug Resist
Updat 2005;8:131–46.
[8] Jung Y, Lippard SJ. Direct cellular responses to platinum-induced DNA damage.
Chem Rev 2007;107:1387–407.
[9] Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level.
Oncol Rep 2003;10:1663–82.
[10] Cvitkovic E, Bekradda M. Oxaliplatin: a new therapeutic option in colorectal
cancer. Semin Oncol 1999;26:647–62.
[11] O’Dwyer PJ, Stevenson JP, Johnson SW. Clinical pharmacokinetics and
administration of established platinum drugs. Drugs 2000;59:19–27.
[12] Hannon MJ. Metal-based anticancer drugs: from a past anchored in platinum
chemistry to a post-genomic future of diverse chemistry and biology. Pure
Appl Chem 2007;79:2243–61.
[13] Antman KH. Introduction: the history of arsenic trioxide in cancer therapy.
Oncologist 2001;6:1–2.
[14] Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, et al.
Resistance against novel anticancer metal compounds: differences and
similarities. Drug Resist Updat 2008;11:1–16.
[15] Clarke MJ, Zhu F, Frasca DR. Non-platinum chemotherapeutic
metallopharmaceuticals. Chem Rev 1999;99:2511–33.
[16] Golcu A, Tumer M, Demirelli H, Wheatley RA. Cd(II) and Cu(II) complexes of
polydentate Schiff base ligands: synthesis, characterization, properties and
biological activity. Inorg Chim Acta 2005;358:1785–97.
[17] Wong ELM, Fang GS, Che CM, Zhu N. Highly cytotoxic iron(II) complexes with
pentadentate pyridyl ligands as a new class of anti-tumor agents. Chem
Commun 2005;36:4578–80.
[18] Marzano C, Pellei M, Tisato F, Santini C. Copper complexes as anticancer
agents. Anticancer Agents Med Chem 2009;9:185–211.
[19] Rademaker-Lakhai JM, van den Bongard D, Pluim D, Beijnen JH, Schellens JH. A
Phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-
tetrachlororuthenate, a novel ruthenium anticancer agent. Clin Cancer Res
2004;10:3717–27.
[20] Hartinger CG, Jakupec MA, Zorbas-Seifried S, Groessl M, Egger A, Berger W,
et al. KP1019, a new redox-active anticancer agent-preclinical development
and results of a clinical phase I study in tumor patients. Chem Biodivers
2008;5:2140–55.
[21] Antonarakis ES, Emadi A. Ruthenium-based chemotherapeutics: are they
ready for prime time? Cancer Chemother Pharmacol 2010;66:1–9.
[22] Koiri RK, Trigun SK, Mishra L, Pandey K, Dixit D, Dubey SK. Regression of
Dalton’s lymphoma in vivo via decline in lactate dehydrogenase and induction
of apoptosis by a ruthenium(II)-complex containing 4-carboxy N-
ethylbenzamide as ligand. Invest New Drugs 2009;27:503–16.
[23] Trigun SK, Koiri RK, Mishra L, Dubey SK, Singh S, Pandey P. Ruthenium complex
as enzyme modulator: modulation of lactate dehydrogenase by a novel
ruthenium(II) complex ontaining 4-carboxy N-ethylbenzamide as a ligand.
Curr Enzyme Inhib 2007;3:243–53.
[24] Clarke MJ. Ruthenium metallopharmaceuticals. Coord Chem Rev
2003;236:209–33.
[25] Allardyce CS, Dyson PJ. Ruthenium in medicine: current clinical uses and
future prospects. Platinum Met Rev 2001;45:62–9.
[26] Pongratz M, Schluga P, Jakupec MA, Arion VB, Hartinger CG, Allmaier G, et al.
Transferrin binding and transferrin-mediated cellular uptake of the ruthenium
coordination compound KP1019, studied by means of AAS, ESI-MS and CD
spectroscopy. J Anal At Spectrom 2004;19:46–51.
[27] Domotor O, Hartinger CG, Bytzek AK, Kiss T, Keppler BK, Enyedy EA.
Characterization of the binding sites of the anticancer ruthenium(III)
complexes KP1019 and KP1339 on human serum albumin via competition
studies. J Biol Inorg Chem 2013;18:9–17.
[28] Dyson PJ, Sava G. Metal based anti tumor drugs in the post genomic era. Dalton
Trans 2006;16:1929–33.
[29] Bruijnincx PCA, Sadler PJ. New trends for metal complexes with anticancer
activity. Curr Opin Chem Biol 2008;12:197–206.
[30] Zhang J, Zhang F, Li H, Liu C, Xia J, Ma L, et al. Recent progress and future
potential for metal complexes as anticancer drugs targeting G-quadruplex
DNA. Curr Med Chem 2012;19:2957–75.
[31] Chatterjee S, Kundu S, Bhattacharyya A, Hartinger CG, Dyson PJ. The
ruthenium(II) arene compound RAPTA-C induces apoptosis in EAC cells
through mitochondrial and p53-JNK pathways. J Biol Inorg Chem
2008;13:49–55.
[32] Groessl M, Hartinger CG. Anticancer metallodrug research analytically
painting the ‘‘omics’’ picture-current developments and future trends. Anal
Bioanal Chem 2013;405:1791–808.
[33] Dyson PJ. Systematic design of a targeted organometallic antitumour drug in
pre-clinical development. CHIMIA Int J Chem 2007;61:698–703.
[34] Jakupec MA, Reisner E, Eichinger A, Pongratz M, Arion VB, Galanski M, et al.
Redoxactive antineoplastic ruthenium complexes with indazole: correlation of
in vitro potency and reduction potential. J Med Chem 2005;48:2831–7.
[35] Smalley KS, Contractor R, Haass NK, Kulp AN, Atilla-Gokcumen GE, Williams
DS, et al. An organometallic protein kinase inhibitor pharmacologically
activates p53 and induces apoptosis in human melanoma cells. Cancer Res
2007;67:209–17.
[36] Dougan SJ, Habtemariam A, McHale SE, Parsons S, Sadler PJ. Catalytic
organometallic anticancer complexes. Proc Natl Acad Sci USA
2008;105:11628–33.
[37] Sava G, Jaouen G, Hillard EA, Bergamo A. Targeted therapy vs. DNA-adduct
formation-guided design: thoughts about the future of metal-based anticancer
drugs. Dalton Trans 2012;41:8226–34.
[38] Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect.
Cancer Res 2006;66:8927–30.
[39] Koiri RK, Trigun SK, Dubey SK, Singh S, Mishra L. Metal Cu(II) and Zn(II)
bipyridyls as inhibitors of lactate dehydrogenase. Biometals 2008;21:117–26.
[40] Pizarro AM, Habtemariam A, Sadler PJ. Activation mechanisms for
organometallic anticancer complexes. Top Organomet Chem 2010;32:21–56.
[41] Suss-Fink. Arene ruthenium complexes as anticancer agents. Dalton Trans
2010;39:1673–88.
[42] Mishra L, Singh AK, Trigun SK, Singh SK, Pandey SM. Anti HIV and cytotoxic
ruthenium (II) complexes containing flavones: biochemical evaluation in mice.
Ind J Exp Biol 2004;42:660–6.
[43] Kasprzaka MM, Szmigierob L, Zynera E, Ochocki J. Anticancer activity in vitro
of two novel ruthenium(II) complexes with flavanone-based ligands that
overcome cisplatin resistance in human bladder carcinoma cells. J Inorg
Biochem 2011;105:518–24.
[44] Schluga P, Hartinger CG, Egger A, Reisner E, Galanski M, Jakupec MA, et al.
Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of
physiological reductants on their binding to GMP. Dalton Trans
2006;14:1796–802.
[45] Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol
2001;108:671–80.
[46] Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular
regulation to clinical use. Pharmacol Rev 2006;58:488–520.
[47] Savai R, Pullamsetti SS, Banat GA, Weissmann N, Ghofrani HA, Grimminger F,
et al. Targeting cancer with phosphodiesterase inhibitors. Expert Opin Invest
Drugs 2010;19:117–31.
[48] Zhu B, Vemavarapu L, Thompson WJ, Strada SJ. Suppression of cyclic GMP
specific phosphodiesterase 5 promotes apoptosis and inhibits growth in HT29
cells. J Cell Biochem 2005;94:336–50.
[49] Tinsley HN, Gary BD, Keeton AB, Zhang W, Abadi AH, Reynolds RC, et al.
Sulindac sulfide selectively inhibits growth and induces apoptosis of human
R.K. Koiri et al. / Medical Hypotheses 80 (2013) 841–846 845

6. breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP,
and activation of protein kinase G. Mol Cancer Ther 2009;8:3331–40.
[50] Hu J, Ljubimova JY, Inoue S, Konda B, Patil R, Ding H, et al. Phosphodiesterase
type 5 inhibitors increase herceptin transport and treatment efficacy in mouse
metastatic brain tumor models. PLoS One 2010;5:e10108.
[51] Jedlitschky G, Burchell B, Keppler D. The multidrug resistance protein 5
functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem
2000;275:30069–74.
[52] Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, et al.
Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev
2000;52:375–414.
[53] Kumazoe M, Sugihara K, Tsukamoto S, Huang Y, Tsurudome Y, Suzuki T, et al.
67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis.
J Clin Invest 2013;123:787–99.
[54] Yang CS, Wang H. Cancer therapy combination: green tea and a
phosphodiesterase 5 inhibitor? J Clin Invest 2013;123:556–8.
[55] Khairallah M, Khairallah RJ, Young ME, Allen BG, Gillis MA, Danialou G, et al.
Sildenafil and cardiomyocyte-specific cGMP signaling prevent
cardiomyopathic changes associated with dystrophin deficiency. Proc Natl
Acad Sci USA 2008;105:7028–33.
[56] Thompson WJ, Piazza GA, Li H, Liu L, Fetter J, Zhu B, et al. Exisulind induction of
apoptosis involves guanosine 30
,50
-cyclic monophosphate phosphodiesterase
inhibition, protein kinase G activation, and attenuated – catenin. Cancer Res
2000;60:3338–42.
[57] Shailubhai K, Yu HH, Karunanandaa K, Wang JY, Eber SL, Wang Y, et al.
Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse
and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.
Cancer Res 2000;60:5151–7.
[58] Wu CF, Bishopric NH, Pratt RE. Atrial natriuretic peptide induces apoptosis in
neonatal rat cardiac myocytes. J Biol Chem 1997;272:14860–6.
[59] Guh JH, Hwang TL, Ko FN, Chueh AC, Lai MK, Teng CM. Antiproliferative effect
in human prostatic smooth muscle cells by nitric oxide donor. Mol Pharmacol
1998;53:467–74.
[60] Chen JJ, Sun YL, Tiwari AK, Xiao ZJ, Sodani K, Yang DH, et al. PDE5 inhibitors,
sildenafil and vardenafil, reverse multidrug resistance by inhibiting the efflux
function of multidrug resistance protein 7 (ATP-binding Cassette C10)
transporter. Cancer Sci 2012;103:1531–7.
[61] Ding PR, Tiwari AK, Ohnuma S, Lee JWKK, An X, Dai CL, et al. The
phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P-
glycoprotein transporter. PLoS One 2011;6:e19329.
[62] Shi Z, Tiwari AK, Shukla S, Robey RW, Singh S, Kim IW, et al. Sildenafil reverses
ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. Cancer Res
2011;71:3029–41.
846 R.K. Koiri et al. / Medical Hypotheses 80 (2013) 841–846