Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Abstract

Galiximab (anti-CD80 monoclonal antibody) is a primatized (human IgG1 constant regions and cynomologus macaque variable regions) monoclonal antibody that is currently in clinical trials. Galiximab inhibits tumor cell proliferation through possibly cell signaling-mediated effects. Thus, we hypothesized that galiximab may signal the tumor cells and modify intracellular survival/antiapoptotic pathways such as the NF-kB pathway. This hypothesis was tested using various CD80þ Burkitt B-NHL (non-Hodgkin lymphomas)cell lines as models. Treatment of B-NHL cells with galiximab (25-100 mg/mL) resulted in significant inhibition of NF-kB activity and its target resistant factors such as YY1, Snail, and Bcl-2/Bcl-XL. Treatment of B-NHL cells with galiximab sensitized the tumor cells to both cis-diamminedichloroplatinum(II) (CDDP)-and TRAILinduced apoptosis. The important roles of YY1-and Snail-induced inhibition by galiximab in the sensitization to CCDP and TRAIL were corroborated following transfection of Raji cells with YY1 or Snail short interfering RNA. The transfected cells were shown to become sensitive to both CCDP-and TRAIL-induced apoptosis in the absence of galiximab. Furthermore, knockdown of YY1 or Snail inhibited Bcl-XL. The involvement of Bcl-XL inhibition in sensitization was corroborated by the use of the pan-Bcl-2 inhibitor 2MAM-3 whereby the treated cells were sensitive to both CDDP-and TRAIL-induced apoptosis. These findings show that galiximab inhibits the NF-kB/Snail/YY1/Bcl-XL circuit that regulates drug resistance in B-NHL and in combination with cytotoxic drugs results in apoptosis. The findings also support the therapeutic application of the combination of galiximab and cytotoxic drugs in the treatment of drug-resistant CD80-positive B-cell malignancies.

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

“…Since Snail transcription is directly activated by YY1 [136], we can hypothesize that RKIP eliminates tumor EMT characteristics by acting as a negative regulator of the NF-κB/YY1/Snail circuit [137]. These findings highlight the significance of NF-κB/YY1/Snail circuitry targeting in cancer by various molecules with RKIP-inducing activities for reversal of EMT transformation [74,123,138,139]. Last, but not least, RKIP upregulation after Snail knockdown has also been shown to reduce the expression of colon cancer stem cell (CSC) markers leading to reversal of EMT [140].…”

“…The de-repression of death receptor transcription by RKIP-promoting drugs (NPI-0052, DETA/NO, etc. ), or RKIP overexpression abrogates tumor resistance to TRAIL and Fas-ligand (FasL)-mediated apoptosis [26,31,34,74,80,139,179,180,181,182,183,184,185]. Indeed, YY1 levels have been found inversely correlated with DR5, Fas, and RKIP expressions in multiple cancer tissues [30,73,186,187].…”

Combined Delivery and Anti-Cancer Activity of Paclitaxel and Curcumin Using Polymeric Micelles

“…10 11 Curcumin has been shown to suppress the activation of NF-B induced by various inflammatory stimuli through inhibition of the activation of I B kinase (IKK), which is needed for NF-B activation. 12 Based on the above information, we hypothesized that Cur could improve therapeutic outcomes for PTX. The degree of water solubility has a great impact on the clinical applications of drugs.…”

Galiximab (anti-CD80)-induced growth inhibition and prolongation of survival in vivo of B-NHL tumor xenografts and potentiation by the combination with fludarabine

“…Inhibition of this pathway resulted downstream in the inhibition of both the metastasis-inducer and resistant transcription factor, SNAIL and the transcription and resistant factor Ying Yang 1 (YY1) and these inhibitory effects led to sensitization of tumor cells to apoptosis by drugs (e.g. CCDP and TRAIL) (17). …”

“…In addition, since galiximab sensitizes tumor cells in vitro to apoptosis by drugs (17), we have also examined in vivo the antitumor effect of galiximab used in combination with fludarabine or doxorubicin. We show here that galiximab exhibits antitumor activity as a single agent in solid and disseminated human lymphoma xenografts in SCID mice.…”