Combination of hyperthermia and bortezomib results in additive killing in mantle cell lymphoma cells

Abstract

The proteasome inhibitor bortezomib exhibits antitumor activity in many malignancies including mantle cell lymphoma (MCL). Unfortunately, many patients fail to respond to treatment or become refractory. Hyperthermia is an effective chemosensitizer that in combination with some chemotherapeutic agents has shown clinical activity in phase II and III studies. The aim of this study was to use MCL cell lines to investigate the potential benefit of combining clinically relevant doses of bortezomib with two different thermal doses (41.8 degrees C/120 min and 44 degrees C/30 min) that mimic the heterogeneity of the temperature distributions achieved within tumors during hyperthermia. Treated tumor cells were assessed for proliferation using the WST-1 assay and for apoptosis by annexin V staining, while heat shock protein (HSP) levels were determined following western blot analysis. Our results demonstrated that MCL cell lines that are sensitive to bortezomib are also thermosensitive and have low basal expression of hsp27, whereas the bortezomib-resistant MCL cell line strongly expresses hsp27 and is thermoresistant. Interestingly, pre-treatment of MCL cell lines with heat at the two different thermal doses, and the transient elevation of hsp27 and hsp70, do not impair their primary sensitivity to bortezomib. Finally, we show that the concurrent treatment of heat and bortezomib results in additive killing in MCL cell lines.In conclusion, these results suggest that the application of bortezomib, under thermal conditions, in mantle cell lymphoma cells may be beneficial and warrants further investigation.

KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia

“…Hyperthermia is reported to be an influential therapeutic procedure which has mild side-effects, and effective cell-killing and apoptosis inducing properties [16,17]. The major problem in hyperthermia is the 'thermotolerance' phenomenon.…”

Magnetic fluid hyperthermia enhances cytotoxicity of bortezomib in sensitive and resistant cancer cell lines

“…11 It is known that hyperthermia can sensitize cells to some anticancer drugs, thereby enhancing their efficacy. 18,19,26,30 This has been attributed to cellular events triggered by hyperthermia, such as changes in membrane fluidity which produce alterations in intracellular drug concentration, cytoskeletal, lysosomal and endoplasmic reticulum changes, inhibition of repair enzymes, impairment of RNA/DNA synthesis, unfolding, and subsequent protein aggregation. 20,[32][33][34] The way in which hyperthermia is applied can intensify some of these cellular events.…”

“…11 Similar observations were made with HT1080, HeLa, H1299, and HCT116 cells exposed to BZ and hyperthermia. 18,19 The mechanism by which hyperthermia enhances BZ cytotoxicity has not been elucidated. However, protein unfolding and subsequent aggregation induced by hyperthermia is considered one of the mechanisms by which hyperthermia sensitizes cells to proteasome inhibition.…”

“…15,16 Recent studies have provided evidence of enhanced efficacy of BZ when used in combination with hyperthermia. 11,[17][18][19] Xu et al showed that hyperthermia using a water bath sensitized resistant breast cancer cells to BZ, resulting in enhanced cell death. 11 Similar observations were made with HT1080, HeLa, H1299, and HCT116 cells exposed to BZ and hyperthermia.…”

Electrospun PLA/MWCNTs composite nanofibers for combined chemo- and photothermal therapy

“…Recently, NIR photothermal agents such as gold (Au) nanorods, carbon nanotubes and quantum dots, have been used as drug carriers for combination of chemo-and thermotherapy and resulted in an enhanced therapeutic efficacy [22][23][24][25]. Hyperthermia can not only kill cancer cells but also increase drug penetration in the tumor site, and increase the drug toxicity [26]. However, most of these nanocarriers are administrated by intravenous injection and followed by non-target accumulation, resulting in sever toxic side-effects and unsatisfactory anticancer efficacy [27,28].…”