Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin’s lymphoma cells

Abstract

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non-Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G 0 /G 1 phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypolinduced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of nonHodgkin's lymphoma.

Effect of citral on the cytotoxicity of doxorubicin in human B-lymphoma cells

“…Its cellular levels could also predict the sensitivity of many B-lymphoma cells (Yeo et al, 2012) and hepatoblastoma HepG2 cells (Luo et al, 2000) to anticancer agents as well as better amplifying apoptotic stimulus than BCL-2 cellular levels. Moreover, inhibiting BCL-XL seems to be the target of potentiating agents in NHL B cell lines (Jazirehi et al, 2003;Li et al, 2008). Taken together, our results demonstrated that citral could potentiate anticancer activity of doxorubicin by up-regulating BAK and down-regulating BCL-XL mRNA expressions.…”

Chemo-sensitizing effects of EP4 receptor-induced inactivation of nuclear factor-κB

“…The mechanism of Pge1-OH that lead to the inhibition of the NF-κB pathway still needs to be elucidated, nonetheless it links the EP4 receptor-induced apoptosis of Ramos cells to modulation of NF-κB activity.The over-expression of proteins of the anti-apoptotic BCL-2 family members, like BCL-xL, provides a common mechanism through which cancer cells gain a survival advantage. Recent research has provided further evidence linking the over-expression of BCL-xL to lymphoma progression as well as to the observed resistance to a wide spectrum of chemotherapeutic agents seen in patients with B-cell lymphoma (Gaidano and Dalla-Favera, 1993;Li et al, 2008). We found that the decreased NF-κB activity, which was due to EP 4 receptor activation, was accompanied by a reduction in the levels of BCL-xL expression in Ramos cells.…”

“…Since Bcl-2 family proteins play a crucial role in the regulation of apoptosis and can also be regulated by NF-κB transcriptional activity (Khoshnan et al, 2000;Li et al, 2008), we further explored the expression of an anti-apoptotic member of the BCL-2 family, BCL-xL. As showed in Fig.…”

Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs

“…ADM, VCR, VP-16, and bortezomib were freshly diluted with growth media, and immediately added along with everolimus to the cell culture media. Cell proliferation was assessed using MTT assays performed as previously described [16]. Interactions between everolimus and other drugs were assessed using isobologram analyses (CalcuSyn Software, Biosoft, Ferguson, MO, USA).…”