Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells

Engesæter, Birgit; Sathermugathevan, Menaka; Hellenes, Tina; Engebråten, Olav; Holm, Ruth; Flørenes, Viví Ann; Mælandsmo, Gunhild Mari

doi:10.4161/cbt.12.1.15714

Cited by 18 publications

(9 citation statements)

References 43 publications

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“…[30][31][32] Previously ours and other studies have suggested that downregulation of XIAP and Survivin increases the sensitivity of melanoma cells to TRAIL treatment in vitro and in vivo. 33,34 Here we show that anisomycin can sensitize melanoma cells to lexatumumab by reducing the levels of XIAP and Livin. Previously it has been shown that cleavage of Livin generate truncated forms of Livin (tLivin) with marked proapoptotic activity in melanomas.…”

Section: Discussionmentioning

confidence: 72%

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

Slipicevic

Øy

Rosnes

et al. 2013

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 72%

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

Slipicevic

Øy

Rosnes

et al. 2013

Cancer Biology & Therapy

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“…Thereby, depletion of available XIAP liberates caspase-3 and -7 to be processed into its active residues as observed in the FEMX-1 cell line, but not in HHMS. We have recently shown that siRNA mediated down regulation of XIAP sensitizes melanoma cells to TRAIL induced cell death, implying an important role of XIAP [38]. Furthermore, Hörnle et al recently showed that activated caspase-3 cleaves XIAP and further enhances the activation of caspase-3 in a positive feedback loop [28].…”

Section: Discussionmentioning

confidence: 97%

Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

et al. 2012

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Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.

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“…In cancer cells, including melanoma, this equilibrium is often skewed in favor of survival, with IAPs being predominant (38, 39). Committing melanoma cells to apoptosis, which would be an ideal outcome for most therapies, therefore requires additional stimuli.…”

Section: Discussionmentioning

confidence: 99%

The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells

Krepler

Chunduru

Halloran

et al. 2013

Clinical Cancer Research

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Purpose Inhibitor of apoptosis proteins (IAPs) promote cancer cell survival and confer resistance to therapy. We report on the ability of second mitochondria-derived activator of caspases (SMAC) mimetic, birinapant, which acts as antagonist to cIAP1 and cIAP2, to restore the sensitivity to apoptotic stimuli such as tumor necrosis factor (TNF)-α in melanomas Experimental Design Seventeen melanoma cell lines, representing five major genetic subgroups of cutaneous melanoma, were treated with birinapant as a single agent or in combination with TNF-α. Effects on cell viability, target inhibition, and initiation of apoptosis were assessed and findings were validated in in 2D, 3D spheroid and in vivo xenograft models. Results When birinapant was combined with TNF-α, strong combination activity, i.e. neither compound was effective individually but the combination was highly effective, was observed in twelve out of eighteen cell lines. This response was conserved in spheroid models, whereas in vivo birinapant inhibited tumor growth without adding TNF-α in in vitro resistant cell lines. Birinapant combined with TNF-α inhibited the growth of a melanoma cell line with acquired resistance to BRAF inhibition to the same extent as in the parental cell line. Conclusions Birinapant in combination with TNF-α exhibits a strong anti-melanoma effect in vitro. Birinapant as a single agent shows in vivo anti-tumor activity, even if cells are resistant to single agent therapy in vitro. Birinapant in combination with TNF-α is effective in a melanoma cell line with acquired resistance to BRAF inhibitors.

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Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells

Cited by 18 publications

References 43 publications

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis

Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

The Novel SMAC Mimetic Birinapant Exhibits Potent Activity against Human Melanoma Cells

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