PMID- 28702823
OWN - NLM
STAT- MEDLINE
DCOM- 20180522
LR  - 20180618
IS  - 1573-675X (Electronic)
IS  - 1360-8185 (Linking)
VI  - 22
IP  - 10
DP  - 2017 Oct
TI  - Etoposide and doxorubicin enhance the sensitivity of triple negative breast 
      cancers through modulation of TRAIL-DR5 axis.
PG  - 1205-1224
LID - 10.1007/s10495-017-1400-4 [doi]
AB  - Death receptor 5 (DR5) is an important target for development of anticancer 
      agents against triple-negative breast cancer (TNBC). Recently, we reported the 
      molecular level details for the modulation of TRAIL-DR5 axis by quinacrine (QC) 
      in breast cancer cells. In this work, the DR5 mediated anticancer potential of 
      topoisomerase inhibitor etoposide (ET) and doxorubicin (DOX) against TNBC has 
      been evaluated. ET and DOX enhanced the DR5 expression in TNBC cells, whereas 
      non-topoisomerase inhibitors pifithrin-alpha (PIF) and dexamethasone (DEX) failed to 
      do so. In the TRAIL pre-treated cells, ET and DOX induced higher apoptosis, 
      indicating their synergistic effect with TRAIL. The molecular docking and 
      molecular dynamics studies showed their ability to stabilize the TRAIL-DR5 
      complex, whereas PIF and DEX failed to do so. The binding energy for TRAIL-DR5 
      complexation in the ternary complexes containing ET (-111.08 kcal/mol) and DOX 
      (-76.35 kcal/mol) were higher than reported binding energy of binary complex 
      (-53.70 kcal/mol). The in silico and in vitro mutational studies highlighted the 
      importance of DR5 residue SerB68 in mediating the receptor-drug interaction. ET 
      and DOX failed to enhance apoptosis in DR5 knockdown (DR5-KD) cells. On the other 
      hand, TRAIL+ET exhibited induction of DR5 and subsequent apoptosis in WT-DR5 
      overexpressed DR5-KD cells, by modulating the mitochondrial intrinsic apoptosis 
      cascade. An induction of apoptosis and DR5 expression was noticed in xenograft 
      mice and in TNBC patient-derived metastatic cells after TRAIL+ET treatment. Thus, 
      data suggests ET and DOX act as DR5 agonistic ligands and enhance the cellular 
      apoptosis in TNBC.
FAU - Das, Sarita
AU  - Das S
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
FAU - Tripathi, Neha
AU  - Tripathi N
AD  - National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, 
      SAS Nagar, Mohali, Punjab, 160062, India.
FAU - Siddharth, Sumit
AU  - Siddharth S
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
FAU - Nayak, Anmada
AU  - Nayak A
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
FAU - Nayak, Deepika
AU  - Nayak D
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
FAU - Sethy, Chinmayee
AU  - Sethy C
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India.
FAU - Bharatam, Prasad V
AU  - Bharatam PV
AD  - National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, 
      SAS Nagar, Mohali, Punjab, 160062, India.
FAU - Kundu, Chanakya Nath
AU  - Kundu CN
AD  - Cancer Biology Division, KIIT School of Biotechnology, KIIT University, 
      Campus-11, Patia, Bhubaneswar, Odisha, 751024, India. cnkundu@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Doxorubicin/*pharmacology
MH  - Etoposide/*pharmacology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Molecular Docking Simulation
MH  - Protein Binding/drug effects
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - TNF-Related Apoptosis-Inducing Ligand/*metabolism
MH  - Triple Negative Breast Neoplasms/*drug therapy/metabolism/pathology
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Death receptor
OT  - Doxorubicin
OT  - Etoposide
OT  - Molecular docking
OT  - Molecular dynamics
OT  - TNBC
OT  - TRAIL
EDAT- 2017/07/14 06:00
MHDA- 2018/05/23 06:00
CRDT- 2017/07/14 06:00
PHST- 2017/07/14 06:00 [pubmed]
PHST- 2018/05/23 06:00 [medline]
PHST- 2017/07/14 06:00 [entrez]
AID - 10.1007/s10495-017-1400-4 [pii]
AID - 10.1007/s10495-017-1400-4 [doi]
PST - ppublish
SO  - Apoptosis. 2017 Oct;22(10):1205-1224. doi: 10.1007/s10495-017-1400-4.