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© 2003 American Society for Clinical Oncology
Overcoming Drug Resistance in Multiple Myeloma: The Emergence of Therapeutic Approaches to Induce ApoptosisFrom the Institute for Myeloma and Bone Cancer Research; and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. Address reprint requests to Hank H. Yang, MD, PhD, Institute for Myeloma and Bone Cancer Research, 1875 Century Park East, Suite 300, Los Angeles, CA 90067; e-mail: hyang{at}myelomasource.org.
Drug resistance remains a major clinical challenge for cancer treatment. Early studies suggested that overexpression of P-glycoprotein was a major contributor to the chemotherapy resistance of myeloma cells and other tumor cells. Attempts in several clinical studies to reverse multidrug resistance protein (MDR) by using MDR modulators have not yet generated promising results. Recently, the emerging knowledge about the importance of overcoming antiapoptosis and drug resistance in treating a variety of malignancies, including multiple myeloma (MM), raises new hope of improving the treatment outcome for patients with cancer. The therapeutic value of targeting therapies that aim to reverse the antiapoptotic process in MM cells has been explored in a number of experimental systems, and the results have been promising. The proteasome inhibitor PS-341 is a new specifically targeted proapoptotic therapy that has been tested in clinical studies. The results indicate that PS-341 alone is an effective therapy for patients with MM who experience disease relapse. Recent in vitro data also demonstrate that PS-341 can markedly sensitize chemotherapy-resistant MM cells to various chemotherapeutic agents. On the basis of these encouraging results, clinical studies are underway to test the efficacy of PS-341 and chemotherapeutic agents as combination therapy in treating patients with refractory and relapsed MM.
MANY MULTIPLE myeloma (MM) patients are initially responsive to chemotherapy. However, they later experience disease relapse because tumor cells acquire drug resistance. Drug resistance is a considerable obstacle to successful treatment for these patients.1 There are several mechanisms by which tumor cells develop resistance to cytotoxic agents. One mechanism is mediated by drug transporter proteins, such as P-glycoprotein (P-gp) or multidrug resistance protein 1 (MDR1),2 MDR-associated protein (MRP),3 breast cancer resistance protein (BCRP),4 and lung resistance–related protein (LRP; a major vault protein).5 Another mechanism is related to resistance to apoptosis (programmed cell death) of tumor cells induced by cytotoxic agents and radiation.6 The cellular molecules involved in this mechanism include overexpression of antiapoptotic proteins, such as B-cell leukemia protein 2 (Bcl-2), Bcl-XL, A1/Bfl1, and mutations in the p53 protein. Recently, increased activity of the transcription factor nuclear factor kappa B (NF-  B) has emerged as a major mechanism for tumor cells to acquire chemotherapy resistance in response to cytotoxic agents or tumor necrosis factor alpha (TNF- ).7 Therapeutic interventions that can lower the threshold for apoptosis of tumor cells could become useful approaches to treat cancer when used as either a single agent or in combination with other therapeutic modalities, such as chemotherapy and radiation.
The term MDR describes the phenomenon by which tumor cells become cross-resistant to several structurally unrelated chemotherapeutic agents after exposure of cells to a single cytotoxic drug.2 One of the most important mechanisms of MDR is mediated by P-gp, which encodes a 170-kd transmembrane glycoprotein. P-gp is capable of extruding a wide variety of large heterocyclic compounds, including anthracyclines, vinca alkaloids, and epipodophyllotoxins, that are frequently used for treating hematologic malignancies. Like P-gp, MRP can also export chemotherapeutic drugs that are glutathione-S-conjugated.3,8 The MRP family includes seven members9; MRP1 and MRP2 can lead to the extrusion of anthracyclines and vinca alkaloids. However, only MRP1, not MRP2, can export methotrexate. Conversely, only MRP2 can cotransport platin salts. Overexpressed MRP4 protein can lead to cellular resistance to methotrexate, whereas MRP5 expression provides resistance to nucleotide analogues, such as mercaptopurine and thioguanine. The function of BCRP was initially examined in MDR1-negative and MRP1-negative breast cancer and colon cancer cell lines resistant to anthracycline and mitoxantrone, respectively.10 Overexpression of BCRP results in cross-resistance to mitoxantrone, daunorubicin, and topotecan, but not to microtubular inhibitors, such as paclitaxel and vinblastine.4 LRP is a major nuclear vault protein that assembles as a barrel-shaped structure.5 It forms central plugs of the nuclear pore complexes and functions to block the transport of drugs from the cytoplasm to the nucleus. The spectrum of cross-resistance of LRP is wide, covering the classical MDR phenotype as well as the platinol- and melphalan-resistant phenotypes.11 Acquired drug resistance in MM cells manifests as a multidrug-resistant phenotype.1,12 P-gp does not seem to be expressed de novo in myeloma cells obtained from patients before they receive chemotherapy. The expression of P-gp has not been shown to be elevated in patients treated with melphalan either.13 However, P-gp expression does increase in approximately 75% of patients treated with vincristine, doxorubicin, and dexamethasone (VAD).13,14 The likelihood of P-gp expression in myeloma cells correlates with the cumulative dose of doxorubicin and vincristine the patient has received. The alternative drug-efflux protein MRP has not been found to be overexpressed in MM cells.15,16 BCRP expression was found more frequently in acute myelogenous leukemia (AML), melanoma, and adenocarcinomas of the digestive tract, endometrium, and lung.17 It also was found to be expressed in the mitoxantrone-selected human MM cell line 822618; however, its clinical relevance in patients with MM remains to be validated. LRP is found to be expressed in approximately half of patients with MM, and its expression is associated with a poor response to melphalan-based induction chemotherapy and shorter overall survival duration.19 The response rate was higher (87%) for patients without LRP expression than for those with LRP expression (54%). Thus, LRP can be used as an important genetic marker for predicting poor therapeutic response and outcome. LRP was found to be expressed more frequently in patents with p53 deletion and P-gp overexpression.20 LRP and P-gp might share a similar regulatory mechanism mediated by p53. Inhibition of P-gp activity has become a major focus in clinical studies, and several MDR modulators have been used to reverse drug resistance in an attempt to improve treatment outcome of patients with MM. A phase I/II study was conducted using the MDR modulator verapamil, in combination with VAD, to treat patients with refractory MM.21 An approximately 50% partial response was found in the study, but this combined therapeutic strategy resulted in significant cardiac toxicity. Dalton et al22 tried to minimize this side effect by using lower doses of verapamil in combination with VAD to treat patients with MM in a randomized phase III trial. Unfortunately, the study showed no therapeutic benefit from the suboptimal dose of verapamil. Similar disappointing results were documented for another MDR modulator, quinine. Recently, we published the results of a phase III Southwestern Oncology Group trial in which the treatment outcome of VAD with prednisone was compared with VAD with prednisone and oral quinine in previously untreated patients with MM.23 Progression-free and overall survival rates were similar between the two arms. Cyclosporine is another MDR modulator that has been used together with the VAD regimen in treating MM.24 Among 21 tested patients, 58% of patients identified to have MDR1-positive plasma cells responded to the treatment, whereas only 31% of MDR1-negative patients responded. However, the addition of cyclosporine to chemotherapy seems to be more toxic, with a high incidence of neurotoxicity and myelosuppression. Valspodar (also called PSC833) is an oral form of cyclosporine D derivative25 and is approximately five-fold more potent than cyclosporine in inhibiting P-gp. Unlike the early generation MDR modulators that are the substrates and competitive inhibitors of P-gp, valspodar is a noncompetitive inhibitor of P-gp. It binds to P-gp with high affinity but cannot be transported by P-gp. Its therapeutic value has been tested in 22 patients with refractory MM in a phase I trial in which oral valspodar was used with VAD.26 Overall, 10 of 22 patients (45%) showed partial response to the treatment, and among them, partial responses were observed in four of eight patients who had melphalan-refractory disease and six of 12 patients who had VAD-refractory disease. Valspodar seems to be less toxic and immunosuppressive than cyclosporine. Its dose limiting toxicity is cerebellar ataxia, which is dose-dependent and reversible.27 Valspodar has significant drug interactions with MDR-related cytotoxic agents. Valspodar can inhibit P-gp in the liver and kidneys, which is required for serum drug excretion. For example, concomitant use of valspodar was shown to increase the area under the curve of doxorubicin and reduce the dose of doxorubicin (by 50% to 75%) needed for its therapeutic efficacy. Recent data from phase III trials of other hematologic malignancies, including AML, have failed to demonstrate the benefit of valspodar when it was added to the chemotherapy regimen in treating relapsed disease.28 A phase III trial conducted by the Cancer and Leukemia Group B showed excessive toxicity and death from valspodar treatment in previously untreated elderly patients with AML, resulting in the premature closure of the study.29 MDR derived from P-gp expression is only one of several identified mechanisms of drug resistance. Tumor cells can overexpress the drug-target proteins in response to treatment with chemotherapeutic agents or create mutations that interfere with the interaction between a drug and its target protein. Examples include resistance to methotrexate, epipodophyllotoxins, mitoxantrone, and anthracyclines.30 More recently, the studies have focused on the inhibition of apoptosis as the so-called de novo mechanism of drug resistance.
Apoptosis is a well-organized process of cell death preprogrammed inside the cell.31 Apoptosis can be initiated either by activation of death receptors on the cell surface membrane (referred to as the extrinsic pathway) or through a series of cellular events primarily processed at mitochondria (referred to as the intrinsic pathway). Once the apoptotic process is started, it eventually leads to the activation of the caspase cascade that in turn activates the proteolytic degradation of a variety of important proteins and leads to the destruction of DNA, resulting in the typical biochemical and morphologic changes characteristic of apoptotic cell death32 (Fig 1  ). Apoptosis has been shown to be important for tumorigenesis and cancer treatment. Defects in apoptosis can result in the expansion of a population of neoplastic cells. However, because the death of tumor cells induced by chemotherapy and radiotherapy is largely mediated by activation of apoptosis,33 inhibition of apoptosis will make tumor cells resistant to antitumor treatment. In response to chemotherapy and radiation, tumor cells increase the production of survival proteins that function to protect cells from death by inhibiting apoptosis.34 In the following sections, we will discuss the function and regulation of these survival proteins, with special emphasis placed on the transcription factor NF-B.
The Biology of NF- BApoptotic effects of NF- B.
NF-B is composed of a family of homo- and heterodimeric transcription factors that bind to a common sequence motif called the B site. These dimers include RelA (p65), RelB, c-Rel, NF-B1 (p50/p150), and NF-B2 (p52/p100).35 In most cell types, NF-B is dimerized as a p50/p65 complex. The subunits of NF-B complexes differ from each other by their amino-terminal Rel homology domains—the part of the protein involved in protein dimerization, DNA binding, and interactions with inhibitory factors, such as inhibition of B (IB) proteins. IB proteins contain an N-terminal regulatory domain followed by multiple ankyrin repeats that interact with the Rel homology domain of NF-B through protein-protein interaction. The various IBs (IB, IBß, and IB ) bind to NF-B proteins, covering the nuclear localization signal of NF-B proteins, and thereby prevent their translocation from the cytoplasm to the nucleus. Bcl-3 is another member of the IB family. It interacts with the p50 or p52 homodimers of NF-B in the nucleus and acts as a transcriptional coactivator.
NF-
NF-
NF-
Many cell adhesion molecules, such as E-selectin molecule and VCAM-1, have also been shown to be involved in the angiogenic process.40 The participation of NF-
NF-
Proteasome Inhibition As a Therapeutic Strategy
A number of studies have shown the inhibitory effect of proteasome inhibitors on tumor cell growth and proliferation. Experiments done in vitro using a National Cancer Institute tumor cell line screen assay clearly demonstrated that PS-341 is cytotoxic (median GI50, 6 nmol/L) to a variety of tumor cells including breast, prostate, colon, lung, brain, melanoma, leukemia, and lymphoma.50 PS-341 has also been shown to have potent antitumor activity in animal models, both as a single agent and in combination with agents such as irinotecan, docetaxel, gemcitabine, and cisplatin.49–51
PS-341 has been shown to be quite effective in inhibiting human myeloma cell growth. Hideshima et al52 have demonstrated in vitro that PS-341 can inhibit proliferation through induction of apoptosis of several human MM cell lines, as well as MM cells freshly isolated from patients. We also recently examined the effect of PS-341 on the growth of several MM cell lines and fresh samples from myeloma patients.48 The growth of both chemotherapy-sensitive and chemotherapy-resistant MM cell lines was substantially inhibited by PS-341 treatment. Interestingly, there is a right shift in the dose-response curves for chemotherapy-resistant cell lines, suggesting that the chemotherapy-resistant cell lines seem to be more sensitive to the treatment of PS-341 than do the chemotherapy-sensitive lines. The alteration in NF- The potential therapeutic role of PS-341 in treating MM has also been demonstrated in animal studies. LeBlanc et al53 treated the human MM xenograft mice with PS-341 administered twice weekly for a total of four doses. PS-341–treated mice showed significant inhibition of tumor growth as early as 5 days after the treatment. Some treated mice also showed complete tumor regression at doses of 0.5 and 1.0 mg/kg. Compared with mice in the control group, the mice treated with PS-341 had a prolongation of median survival time (> 40%). Both tumor growth inhibition and mouse survival prolongation were dose-dependent. On the basis of the encouraging results from preclinical studies, several human trials with PS-341 were conducted. Initially, two phase I trials were initiated to examine the safety profile of PS-341 among patients with a variety of advanced malignancies.54 These studies used dosing regimens of once weekly for 4 weeks, twice weekly for 2 weeks, and twice weekly for 4 weeks, resulting in maximum-tolerated doses of 1.8, 1.3, and 1.04 mg/m2, respectively. On the basis of preliminary evidence of activity in myeloma, a phase II multicenter trial was conducted recently using PS-341 to treat patients with relapsed or refractory MM.55 PS-341 was given via intravenous push at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle for as many as eight cycles. Dexamethasone was added if the patient did not respond to PS-341. The results show anti-MM activity, with one-third of patients showing responses, and MM patients are now being enrolled onto a phase III trial.
NF-
Using NF-
The synergy observed between PS-341 and chemotherapeutic agents seems to be cell-type specific.48 Synergistic effects between PS-341 and chemotherapeutic agents were not found when they were used together to treat the T-cell leukemia cell lines NB-4 and U937, B-cell leukemia cell line molt-4, primary effusion lymphoma cell line KS-1, and 293 kidney tumor cell line.48 Similar experiments were also performed on normal unstimulated and stimulated (with 20 nmol/L polyhydroxy acid for 30 minutes) peripheral-blood mononuclear cells and CD34-selected bone-marrow derived mononuclear cells obtained from healthy individuals. Suppression of proliferation in these non-MM cell lines or normal hematopoietic cells was not observed with PS-341 treatment except at higher concentrations (concentration that inhibits 50%, 50 to 75 ng/mL). Moreover, the addition of PS-341 to chemotherapy had minimal synergistic inhibitory effects on cell growth in these same samples. This observation is interesting because the extent of synergy between PS-341 and cytotoxic agents seems to correlate with the baseline levels of NF-
Other than proteasome inhibitors, NF-
Involvement of Other Antiapoptotic Proteins in Drug Resistance
Bcl-2.
The intrinsic apoptotic pathway processed at the mitochondrial level is regulated by the members of Bcl-2 family70 (Fig 1
Surprisingly, the antiapoptotic effects of Bcl-2 could also be reversed by proteasome inhibitors, even though the antiapoptotic effects of Bcl-2 are believed to be independent of NF-
IL-6.
IL-6 is an important growth factor for myeloma cells. IL-6 also promotes survival of myeloma cells by blocking the apoptotic stimuli.80 The details of IL-6 antiapoptosis signal transduction pathways are not yet fully understood. Some newly emergent evidence suggests that this cytokine might work through either mitogen-activated protein kinase (MAPK) signaling81 or the Janus kinase (JAK) signal transduction and activation of signal transducer and activator of transcription 3 (STAT3) pathways82 (Fig 1
Unlike the IL-6–induced p42/44 MAPK pathway, which can be inhibited by PS-341, JAK-STAT3 signaling was found to be unresponsive to PS-341 treatment.52 However, the antiapoptotic effects of JAK-STAT3 signaling could be reversed by other strategies. For example, a dominant negative STAT3 protein was introduced into U266 myeloma cells via transfection to block JAK-STAT3 signaling.88 JAK-STAT signaling may also be inhibited via a pharmacologic approach, such as by applying a specific inhibitor of JAK family kinases, AG49088 (Table 1
Cell adhesion and angiogenesis.
The extracellular contacts of myeloma cells are able to modulate the cellular response to cytotoxic agents and contribute to chemotherapy resistance of MM cells. Dalton et al89 described this phenomenon as cell adhesion–mediated drug resistance. Unlike MDR, which is usually acquired by the tumor cells of hematologic malignancies, cell adhesion–mediated drug resistance occurs de novo before the exposure of chemotherapy and radiotherapy.90 The cell adhesion molecule,
In conclusion, drug resistance remains a major challenge in the treatment of MM and other cancers. There is no single therapeutic modality that has been shown clinically to be sufficiently effective in reversing drug resistance of tumor cells. One of the major obstacles is the presence of multiple mechanisms of drug resistance developed in tumor cells that compromises the efficacy of anticancer therapies. MDR mediated by drug-transport proteins represents only part of the evolving accounts of drug resistance. Recent findings on the importance of antiapoptosis for drug resistance raise new hope in treating patients with cancer who develop resistance to chemotherapy or radiotherapy. In fact, like recent developments in molecular studies of tumorigenesis that have been or could be used to design various target-specific anticancer therapies, we should be able to use different target-specific therapeutic interventions to reverse the drug-resistance phenotype of tumor cells. To accomplish this, we first need to identify the clinically applicable surrogate markers for various molecular alterations that underlie the development of drug resistance and use these markers to guide our treatment. In the past, we used the levels of expression of drug-transport proteins to help identify the appropriate MDR-modulators in treating chemotherapy-resistant patients with cancer. Now that the proteasome inhibitor PS-341 and other target-specific proapoptotic therapies are available, we may be able to use the level of NF-
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Hank H. Yang, Millennium Pharmaceuticals Inc; Robert A. Vescio, Millennium Pharmaceuticals Inc; James R. Berenson, Millennium Pharmaceuticals Inc, Cell Therapeutics Inc. Received more than $2,000 a year from a company for either of the last 2 years: Hank H. Yang, Millennium Pharmaceuticals Inc; Robert A. Vescio, Millennium Pharmaceuticals Inc, James R. Berenson, Millennium Pharmaceuticals Inc.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
