Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition

Wen, Jianguo; Feng, Yongdong; Huang, Wan‐Ting; Chen, Haiyun; Liao, Bing; Rice, Lawrence; Preti, Hector Alejandro; Kamble, Rammurti T.; Zu, Youli; Ballon, Douglas; Chang, Chung Che

doi:10.1016/j.leukres.2009.05.024

Cited by 43 publications

(39 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gutierrez and colleagues demonstrated that p38 activation contribute to tamoxifen resistance in ER-positive breast tumors (38). More recently, Wen and colleagues showed that p38 inhibition enhances the sensitivity to arsenic trioxide and bortezomib in multiple myeloma (40). In line with these results, we show that the level of phosphorylated p38a is higher in patients unresponsive to chemotherapy compared with responders, suggesting that p38 activation is correlated with irinotecan resistance in CRC.…”

Section: Discussionsupporting

confidence: 88%

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

et al. 2011

View full text Add to dashboard Cite

Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6-to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both a and b isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38a and p38b, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.

show abstract

Section: Discussionsupporting

confidence: 88%

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In this regard, it is noteworthy that TRAIL, a TNF superfamily member, ligates two types of receptors: death receptors triggering TRAIL-induced apoptosis (TRAIL R1 and TRAIL R2) and decoy receptors that act as sinks for TRAIL and administering ATO to MM patients. More studies showed a synergic effect when ATO is administered in combination with other anti-MM drugs, such as bortezomib, the DNA methylation inhibitor 5-azacytidine and melphalan et al [31][32][33][34] The findings in this study offer a promising and novel strategy, using ATO to activate TRAIL, in the treatment of myelomas, especially those aggressive myeloma subtypes with low expression of TRAIL, such as MS subgroup with reciprocal translocation (4:14) and MF subgroup with reciprocal translocations (14:16) and (14:20).…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Shi

et al. 2010

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…Additionally, ATO activates JNK pathway in ATO-sensitive myeloma cells but not in ATO-insensitive/resistant myeloma cells, which might improve outcome in MM therapy 37. In contrast, ATO activates the p38/MAPK pathway that contributes to resistance to ATO in myeloma cells 38,39. Inhibition of NF-κB activation by ATO was observed to react with a critical cystein in the activation loop of IκB kinase 40.…”

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide-based therapy in relapsed/refractory multiple myeloma patients: a meta-analysis and systematic review

He¹,

Yang²,

Chen³

et al. 2014

OTT

View full text Add to dashboard Cite

Multiple myeloma (MM) is a clonal malignancy characterized by the proliferation of malignant plasma cells in the bone marrow and the production of monoclonal immunoglobulin. Although some newly approved drugs (thalidomide, lenalidomide, and bortezomib) demonstrate significant benefit for MM patients with improved survival, all MM patients still relapse. Arsenic trioxide (ATO) is the most active single agent in acute promyelocytic leukemia, the antitumor activity of which is partly dependent on the production of reactive oxygen species. Due to its multifaceted effects observed on MM cell lines and primary myeloma cells, Phase I/II trials have been conducted in heavily pretreated patients with relapsed or refractory MM. Therapy regimens varied dramatically as to the dosage of ATO and monotherapy versus combination therapy with other agents available for the treatment of MM. Although ATO-based combination treatment was well tolerated by most patients, most trials found that ATO has limited effects on MM patients. However, since small numbers of patients were randomized to different treatment arms, trials have not been statistically powered to determine the differences in progression-free survival and overall survival among the experimental arms. Therefore, large Phase III studies of ATO-based randomized controlled trials will be needed to establish whether ATO has any potential beneficial effects in the clinical setting.

show abstract

Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition

Cited by 43 publications

References 48 publications

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Arsenic trioxide-based therapy in relapsed/refractory multiple myeloma patients: a meta-analysis and systematic review

Contact Info

Product

Resources

About