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Drug resistance in multiple myeloma: approaches to circumvention
1Department of Medicine, Pharmacology, and Biochemistry, H. Lee Moffitt Cancer Center at the University of South Florida, Tampa 33612, USA.
Abstract:
Resistance mechanisms to chemotherapy in multiple myeloma include (1) reduced drug concentrations at the target site of action, (2) alterations in the drug target, and (3) inhibition or prevention of drug-induced apoptosis. Recent advances in understanding resistance mechanisms have resulted in the investigation of novel therapies for the treatment of patients with multiple myeloma. P-glycoprotein is a drug transport protein that decreases intracellular drug concentrations at the target site. Valspodar, a third-generation cyclosporine analog, is an inhibitor of P-glycoprotein that currently is being evaluated to potentially overcome this mechanism of drug resistance. P-glycoprotein inhibitors (also known as chemosensitizers) are being investigated for use in combination with chemotherapeutic agents to enhance the apoptotic effect and prevent resistance at the target site. Other novel approaches involve blocking pathways that result in the expression of antiapoptosis factors. Interleukin-6 is an important growth factor in myeloma and has been implicated in drug resistance via an antiapoptosis effect. In vitro blocking of an interleukin-6-dependent pathway with either a JAK inhibitor (tyrphostin, AG490) or STAT3 dominant negative (STAT3-DN) reduced expression of Bcl-xL (an antiapoptosis protein), increased spontaneous apoptosis, and enhanced sensitivity to Fas-mediated apoptosis. In conclusion, several cellular mechanisms reduce the response to drug therapy in multiple myeloma. Future treatment approaches for this condition most likely will involve combinations of agents to enhance response or prevent resistance.
Insights
Novel therapies are being developed to overcome chemotherapy resistance in multiple myeloma by targeting drug efflux and apoptosis pathways. Combinations of agents show promise for enhancing treatment response and preventing resistance.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Multiple myeloma exhibits resistance to chemotherapy through mechanisms like reduced drug concentration, altered drug targets, and inhibited apoptosis.
- P-glycoprotein (P-gp) efflux pumps decrease intracellular chemotherapy concentrations, contributing to treatment failure.
- Interleukin-6 (IL-6) signaling promotes myeloma cell survival and chemoresistance by upregulating anti-apoptotic factors.
Purpose of the Study:
- To review current understanding of chemotherapy resistance mechanisms in multiple myeloma.
- To explore novel therapeutic strategies targeting P-gp and IL-6 pathways for overcoming resistance.
Main Methods:
- Investigating P-glycoprotein inhibitors (chemosensitizers) like Valspodar to reverse P-gp mediated drug efflux.
- Evaluating the effects of blocking IL-6 signaling pathways using JAK inhibitors (e.g., AG490) and STAT3 dominant negatives (STAT3-DN) in vitro.
- Assessing the impact on anti-apoptotic protein expression (Bcl-xL) and apoptosis induction.
Main Results:
- P-glycoprotein inhibitors aim to increase intracellular drug levels and enhance apoptosis.
- Blocking IL-6 signaling reduced Bcl-xL expression, increased spontaneous apoptosis, and sensitized cells to Fas-mediated apoptosis.
- In vitro studies demonstrated that targeting IL-6 pathways can overcome resistance mechanisms.
Conclusions:
- Multiple myeloma chemoresistance involves complex cellular mechanisms.
- Future treatments will likely combine agents to enhance efficacy and prevent resistance.
- Targeting drug efflux and survival pathways represents a promising strategy for improving multiple myeloma therapy.