Targeted Apoptotic Effects of Thymoquinone and Tamoxifen on XIAP Mediated Akt Regulation in Breast Cancer

Shashi Rajput, Prashanth Kumar Bhusetty Nagesh, Siddik Sarkar, Subhasis Das, Belal Azab, Prasanna K. Santhekadur, Swadesh K. Das, Luni Emdad, Devanand Sarkar, Paul B. Fisher, Mahitosh Mandal

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

X-linked inhibitor of apoptosis protein (XIAP) is constitutively expressed endogenous inhibitor of apoptosis, exhibit its antiapoptotic effect by inactivating key caspases such as caspase-3, caspase-7 and caspase-9 and also play pivotal role in rendering cancer chemoresistance. Our studies showed the coadministration of TQ and TAM resulting in a substantial increase in breast cancer cell apoptosis and marked inhibition of cell growth both in vitro and in vivo. Anti-angiogenic and anti-invasive potential of TQ and TAM was assessed through in vitro studies. This novel combinatorial regimen leads to regulation of multiple cell signaling targets including inactivation of Akt and XIAP degradation. At molecular level, TQ and TAM synergistically lowers XIAP expression resulting in binding and activation of caspase-9 in apoptotic cascade, and interfere with cell survival through PI3-K/Akt pathway by inhibiting Akt phosphorylation. Cleaved caspase-9 further processes other intracellular death substrates such as PARP thereby shifting the balance from survival to apoptosis, indicated by rise in the sub-G1 cell population. This combination also downregulates the expression of Akt-regulated downstream effectors such as Bcl-xL, Bcl-2 and induce expression of Bax, AIF, cytochrome C and p-27. Consistent with these results, overexpression studies further confirmed the involvement of XIAP and its regulatory action on Akt phosphorylation along with procaspase-9 and PARP cleavage in TQ-TAM coadministrated induced apoptosis. The ability of TQ and TAM in inhibiting XIAP was confirmed through siRNA-XIAP cotransfection studies. This novel modality may be a promising tool in breast cancer treatment.

Original languageEnglish (US)
Article numbere61342
JournalPloS one
Volume8
Issue number4
DOIs
StatePublished - Apr 17 2013

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X-Linked Inhibitor of Apoptosis Protein
tamoxifen
Tamoxifen
breast neoplasms
apoptosis
Caspase 9
Breast Neoplasms
Apoptosis
Phosphorylation
proteins
caspase-9
Cells
Cell signaling
Caspase 7
Oncology
Cell growth
Cytochromes
Caspases
phosphorylation
caspase-7

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Targeted Apoptotic Effects of Thymoquinone and Tamoxifen on XIAP Mediated Akt Regulation in Breast Cancer. / Rajput, Shashi; Bhusetty Nagesh, Prashanth Kumar; Sarkar, Siddik; Das, Subhasis; Azab, Belal; Santhekadur, Prasanna K.; Das, Swadesh K.; Emdad, Luni; Sarkar, Devanand; Fisher, Paul B.; Mandal, Mahitosh.

In: PloS one, Vol. 8, No. 4, e61342, 17.04.2013.

Research output: Contribution to journalArticle

Rajput, S, Bhusetty Nagesh, PK, Sarkar, S, Das, S, Azab, B, Santhekadur, PK, Das, SK, Emdad, L, Sarkar, D, Fisher, PB & Mandal, M 2013, 'Targeted Apoptotic Effects of Thymoquinone and Tamoxifen on XIAP Mediated Akt Regulation in Breast Cancer', PloS one, vol. 8, no. 4, e61342. https://doi.org/10.1371/journal.pone.0061342
Rajput, Shashi ; Bhusetty Nagesh, Prashanth Kumar ; Sarkar, Siddik ; Das, Subhasis ; Azab, Belal ; Santhekadur, Prasanna K. ; Das, Swadesh K. ; Emdad, Luni ; Sarkar, Devanand ; Fisher, Paul B. ; Mandal, Mahitosh. / Targeted Apoptotic Effects of Thymoquinone and Tamoxifen on XIAP Mediated Akt Regulation in Breast Cancer. In: PloS one. 2013 ; Vol. 8, No. 4.
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AU - Azab, Belal

AU - Santhekadur, Prasanna K.

AU - Das, Swadesh K.

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