Table Of ContentCancer Sensitizing Agents for Chemotherapy
DRUG RESISTANCE IN COLORECTAL
CANCER: MOLECULAR MECHANISMS
AND THERAPEUTIC STRATEGIES
VOLUME 8
Cancer Sensitizing Agents for Chemotherapy Series
Series Editor: BenjaminBonavida, PhD
Volume1: NitricOxide(Donor/Induced)inChemosensitization
EditedbyBenjaminBonavida,PhD
Volume2: RoleofNutraceuticalsinCancerChemosensitization
EditedbyAlokChandraBhartiandBharatBhushanAggarwal
Volume3: TargetingCellSurvivalPathwaystoEnhanceResponsetoChemotherapy
EditedbyDanielM.Johnson,PhD
Volume4: ProteinKinaseInhibitorsasSensitizingAgentsforChemotherapy
EditedbyZhe-ShengChenandDong-HuaYang
Volume5: BreakingTolerancetoPancreaticCancerUnresponsivenesstoChemotherapy
EditedbyGanjiPurnachandraNagaraju,PhD,DSc
Volume6: ImprovingtheTherapeuticRatioinHeadandNeckCancer
EditedbyRandalJ.Kimple,MD,PhD
Volume7: DrugEffluxPumpsinCancerResistancePathways:FromMolecularRecognitionand
CharacterizationtoPossibleInhibitionStrategiesinChemotherapy
EditedbyAlejandroSosnik,PhDandReinaBendayan,PharmD
Volume8: DrugResistanceinColorectalCancer:MolecularMechanismsandTherapeuticStrategies
EditedChiHinChoandTaoHu
Volume9: NovelTherapiesinHeadandNeckCancer:BeyondtheHorizon
EditedMaieA.St.JohnandNo-HeePark
UpcomingVolumes:
NewTargetingintheReversalofResistantGlioblastomas
EditedbyAliS.Arbab
TerpenoidsAsChemosensitizersAgainstDrug-resistantTumors
EditedbyThomasEfferth
AdvancingApproachestoOvercomingCancerDrugResistance
EditedbyAndrewFreywaldandFrancoVizeacoumar
TherapeuticStrategiestoOvercomeALKResistanceinCancer
EditedbyLucFriboulet
ReversalofGlioblastomaResistancetoChemotherapy
EditedbyRamasamyPaulmuruganandTarikF.Massoud
OvercomingOvarianCancerChemoresistance
EditedbyGoliSamimiandChristinaAnnunziata
EpigeneticRegulationinCancerChemotherapy
EditedbyChunfuWuandLihuiWang
Cancer Sensitizing Agents
for Chemotherapy
DRUG RESISTANCE IN
COLORECTAL CANCER:
MOLECULAR MECHANISMS
AND THERAPEUTIC
STRATEGIES
VOLUME 8
Edited by
C H C
HI IN HO
LaboratoryofMolecularPharmacology,SchoolofPharmacy,SouthwestMedical
University,Luzhou,Sichuan,China
T H
AO U
DepartmentofPharmaceuticalScience,SchoolofPharmacy,Universityof
Maryland,Baltimore,MD,UnitedStates
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Aims and Scope for Series
“Cancer Sensitizing Agents
for Chemotherapy”
Current cancer management strategies The main objective of the proposed series
fail to adequately treat malignancies with “Cancer Sensitizing Agents for Chemother-
chemotherapy, with multivariable dose- apy”istopublishindividualizedandfocused
restrictive factors such as systemic toxicity volumeswherebyeachvolumeiseditedbyan
and multidrug resistance; hence, limiting invited expert Editor(s). Each volume will
therapeuticbenefits,qualityoflife,andcom- dwell on specific chemo-sensitizing agents
plete long-term remission rates. The resis- withsimilartargetingactivities.Thecombina-
tance of cancer cells to anticancer drugs is tion treatment of the sensitizing agent with
one of the major reasons for the failure of chemotherapy may result in a synergistic/
traditional cancer treatments. Cellular com- additive activity and the reversal of tumor
ponents and dysregulation of signaling cellsresistancetodrugs.
pathways contribute to drug resistance. If TheEditor(s)willcompilenonoverlapping
modulated, such perturbations may restore review chapters on reported findings in
thedrugresponseanditsefficacy.Therecent various cancers, both experimentally and
understandingofthemolecularmechanisms clinically,withparticularemphasisonunder-
and targets that are implicated for cancer lying biochemical, genetic, and molecular
chemo-resistance has paved the way to de- mechanisms of the sensitizing agent and the
velop a large battery of small molecules combinationtreatment.
(sensitizing agents) that can target resistant ThescopeoftheSeriesistoprovidescien-
factorsandreducethethresholdofresistance tistsandclinicianswithupdatedandclinical
and, thus, allowing their combination with information that will be valuable in their
chemotherapeutic drugs to be effective and quest to investigate, develop, and apply
toreversethechemo-resistance.Alargevari- novelcombinationtherapiestoreversedrug
etyofchemotherapy-sensitizingagentshave resistanceand,thereby,prolongsurvivaland
been developed and several have been even cure in cancer patients.
showntobeeffectiveinexperimentalmodels
and incancer patients. Dr. Benjamin Bonavida, PhD (SeriesEditor)
v
About the Editors
Chi Hin Cho Tao Hu
Distinguished Professor at the Southwest Medi- Research Fellow at the University of Maryland,
cal University and Emeritus Professor at The Baltimore, MD, United States
ChineseUniversity of Hong Kong, China Doctor Tao Hu obtained his PhD from
Professor Chi Hin Cho was the Chair The Chinese University of Hong Kong. His
Professor in Pharmacology at the University research interests focus on the development
of Hong Kong and also the President and of novel chemotherapeutic agents for the
the Chair of Presidential Council of the treatment of colorectal cancer as well as on
GastrointestinalPharmacologySectionofthe drug metabolism and pharmacokinetics. He
International Union of Basic and Clinical has published more than 20 peer-reviewed
Pharmacology. His research interests focus papers in this field and served as editorial
on drug development for inflammation and boardmemberorreviewerforanumberofin-
cancers in the gastrointestinal tract. He is ternationaljournalsinpharmaceuticalscience.
also the editorial board member and editor
in more than 30 journals and books in the
fieldsofGastroenterologyandPharmacology
and also editor in different world-class pub-
lishers, such as Elsevier, World Scientific,
andKarger.Hehaspublishedmorethan450
peer-reviewedarticlesinhigh-ratedscientific
journalsinpharmacologyandcancerbiology.
xi
About the Series Editor
researchinvestigationshaverangedfromthe
mechanisms of cell-mediated killing and
sensitization of resistant tumor cells to
chemo-/immunotherapies, characterization
of resistant factors in cancer cells, cell-
signaling pathways mediated by therapeutic
anticancer antibodies, and characterization
of a dysregulated NF-κB/Snail/YY1/RKIP/
PTENloopinmanycancersthatregulatecell
survival, proliferation, invasion, metastasis,
and resistance. He has also investigated the
roleofnitricoxideincanceranditspotential
antitumoractivity.Manyoftheabovestudies
are centered on the clinical challenging fea-
turesofcancerpatients’failuretorespondto
Dr.BenjaminBonavida,PhD(SeriesEditor), both conventional and targeted therapies.
is currently Distinguished Research Pro- The development and activity of various
fessor at the University of California, Los chemosensitizing agents and their modes of
Angeles (UCLA). His research career, action to reverse chemo- and immuno-
thus far, has focused on basic immuno- resistance are highlighted in many refereed
chemistry and cancer immunobiology. His publications.
Acknowledgments: The editors wish to an undergraduate student at UCLA and is
acknowledge the excellent editorial assis- knowledgeableinthecancerfield.Theeditors
tance of Ms. Inesa Navasardyan who has also acknowledge the assistance of Rafael
worked diligently in the completion of this Teixeira, Acquisitions Editor for Elsevier,
volume, namely, in both the editing and and Samantha Allard, EditorialProjectMan-
formatting of the various contributions of agerforElsevier,fortheircontinuouscooper-
this volume. Ms. Navasardyan is currently ationduringthedevelopmentofthisbook.
vii
Aims and Scope of the Volume
Colorectal cancer is the third most fre- resistance and to investigate their reversal
quently diagnosed cancer and is also one of strategies,withtheaimtoimprovethether-
the leading causes of cancer-related deaths apeuticoutcomeincolorectalcancerpatients
worldwide. The overall survival of patients in clinics. To this end, this volume titled
with advanced colorectal cancer has been DrugResistanceinColorectalCancer:Molecular
improving over the past decades. However, Mechanisms and Therapeutic Strategies pro-
eventhoughtheresponseratetocurrentsys- vides readers with an in-depth knowledge
temic chemotherapies can reach up to 50%, andquickreferencetothemolecularmecha-
drugresistancehasbeenreportedtodevelop nisms conferring the development of drug
innearlyallpatientswithcolorectalcancer.It resistance in colorectal cancer as well as the
becomes the major problematic issue in the up-to-date therapeutic strategies for its clin-
treatmentofthisdiseaseinthecurrentclini- ical treatment. Based on such knowledge,
cal practice. the investigators would be able to advance
Drugresistancelimitsthetherapeuticeffi- theirunderstandingofthemolecularunder-
cacies of anticancer agents and finally leads lying mechanisms of both the pathogenesis
to chemotherapy failure. In fact, most and progression of colorectal cancer; they
cancer-related deaths are due to this failure wouldalsofurtheridentifynoveltherapeutic
causedbydrugresistancethatoccursduring targetsandstrategiesforthepharmaceutical
thecourseofcancerprogressionandchemo- industrytodevelopbettertherapeuticagents
therapy. More efforts are needed to under- andtreatmentofpatientswithdrug-resistant
stand the molecular mechanisms of drug colorectal cancer.
ix
Preface
Colorectal cancer (CRC) is the third most been discussed in individual chapters. Also,
frequently diagnosed cancer worldwide and serrated lesions in the colon and various
isamongtheleadingcausesofcancer-related cancer cell survival mechanisms including
deaths [1]. Chemotherapyis oneof the main theRac1bareemphasized. Thoseareknown
treatment options for CRC, in particular for tobethemostsignificantmechanismsassoci-
thecanceratadvancedstage.Duetotheavail- atedwiththedevelopmentofdrugresistance
abilityofvariouschemotherapyregimens,the in cancer cells. An understanding of such
overall survival of patients with advanced molecular mechanisms would be helpful
CRC has improved over the past decades. to identify novel therapeutic targets for
However, even though the response rate to advanced CRC. In addition, this book also
current systemic chemotherapies can reach highlights the therapeutic strategies of drug
upto50%,drugresistancehasbeenreported resistance in CRC by targeting the above-
to develop in nearly all CRC patients and mentioned mechanisms, including but not
becomes a major obstacle to the successful limited to inhibitors of drug efflux trans-
treatment in clinical practice [2]. Thus, more porters, hybrid modification of conventional
effortsareneededtounderstandthemolecu- anticancerdrugs,chemicallymodifiedmicro-
lar mechanisms of drug resistance in CRC RNAs, nanotechnology-based drug delivery
and to investigate their reversal strategies, systems, and bioactive phytochemicals. The
with an aim to improve the therapeutic potentialpredictivebiomarkersofdrugresis-
outcomesintheclinics. tanceinCRCarealsocoveredinthisbook.
Thisbookfeaturesaninternationalcollabo- Given the high incidence and mortality
rationwithcontributorsfromNorthAmerica, of CRC in the clinics, the development of
Asia, and Europe, who are investigating on chemotherapy-sensitizing agents and ap-
the front lines of cancer drug resistance proachesishighlyneededinordertoimprove
research, offering their expert opinions and thetherapeuticefficacyandalleviatesystemic
sharing their rich experiences in this field. toxicities, leading to wellbeing and better
Thebook,thus,providesanexcellentreference survivalforCRCpatients.Indeed,theclinical
forreaderswithanoverviewofthemolecular applications of chemotherapy in treating
mechanisms conferring drug resistance in drug-resistantCRCarechallenging,inpartic-
CRC as well as the up-to-date therapeutic ular the combination of chemotherapeutic
strategies for the treatment of this deadly agentswithchemotherapy-sensitizingagents
disease in humans. The alterations and the or other approaches. The compilation of this
involvement of drug efflux transporters, book greatly helps both scientists and
cancer stem cells, microRNAs, and various clinicians to obtain a quick and in-depth
typesofcelldeathsignalingpathwaysinthe understanding of the molecular mechanisms
developmentofdrugresistanceinCRChave of drug resistance in CRC. Such knowledge
xiii
