Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib

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Abstract

Given its role in cellular metabolism, the proteasome could prove to be a critical target that can be exploited in treating cancer. In preclinical studies, several mechanisms for bortezomib’s activity in multiple myeloma cells have been identified (e.g., NF-κB inhibition); antitumor activity with bortezomib has been seen in myeloma patients, thereby supporting the validity of the preclinical work. Similar mechanisms may be in play in solid tumors, and cell culture and xenograft data suggest bortezomib may be active in a wide range of tumor types. One promising possibility is the use of bortezomib for the treatment of chemoresistant tumors. Chemoresistance can be caused by a number of cellular factors; NF-κB is a prominent instigator of chemoresistance, and proteasome inhibition was an effective means of preventing NF-κB activation in myeloma and several solid tumor laboratory studies. However, the inhibition of NF-κB may not be the only mechanism for antitumor activity. This review explores the use of proteasome inhibitors to subvert intrinsic resistance mechanisms, disrupt inducible chemoresistance, or augment the mechanisms of action of standard chemotherapeutics. Thus, in addition to providing another target for anticancer treatment, proteasome inhibition may also provide a means to treat refractory tumors.

Introduction

Chemoresistance is the eventual cause of treatment failure and mortality for most cancers. Some tumor types (e.g., pancreatic cancer) have an intrinsic resistance to existing chemotherapeutics, leading to poor response rates and short-lived responses in those patients who do respond. Resistance can also be acquired on repeated treatment with a chemotherapeutic: for instance, when platinum compounds are used to treat ovarian cancer, a large fraction of tumor cells may be killed on treatment—leading to an initial response—but the selective pressure of the treatment leaves a subset of drug-resistant tumor cells that eventually repopulate the tumor and are resistant to retreatment. Chemotherapy can also paradoxically induce survival pathways that either prevent cells from activating apoptotic pathways or mitigate the damage caused by the chemotherapeutic. Some of these mechanisms may overlap; for example, tumor cells may be intrinsically resistant to chemotherapy because they efficiently induce anti-apoptotic factors in response to chemotherapy (Table 1).

Inhibition of protein degradation through the ubiquitin–proteasome pathway is a unique approach to cancer treatment. The proteasome carries out the regulated degradation of unnecessary or damaged cellular proteins; included in the array of proteins targeted by the proteasome are proteins that regulate cell-cycle progression and apoptosis. Proteasome inhibition adds another unique target to the range of cellular targets for chemotherapy (DNA, the cytoskeleton, and transcription and replication enzymes). Alone, this novel mechanism of action is lethal to many types of cancer cells, and preclinical activity has already been demonstrated in many tumor types, including solid tumors. The dipeptidyl boronic acid bortezomib demonstrated a unique cytotoxicity profile in the National Cancer Institute screen of 60 cell lines. Adams et al. (1) and Teicher et al. (2) were among the first to publish studies exploring the activity of bortezomib. PC-3 prostate cancer cells were sensitive to bortezomib treatment, both in culture and in tumor xenografts (1). In studies by Teicher et al. (2), bortezomib was effective against several breast cancer cell lines, and in mice bearing EMT-6 breast cancer tumors, a single intraperitoneal injection reduced tumor cell survival by 90%. Bortezomib also delayed the growth of Lewis lung carcinoma tumors and reduced the extent of metastatic disease (2). Activity in colorectal cancer has also been demonstrated, and a solid rationale exists for the investigative study of combination therapy with bortezomib and camptothecins in this disease.

A number of studies with bortezomib and other proteasome inhibitors have demonstrated activity alone or in combination in resistant or difficult-to-treat cancers, such as myeloma [3], [4], [5], [6], pancreatic cancer [7], [8], and colon cancer (9). In one study, the effectiveness of bortezomib against cells grown in a monolayer versus those grown in spherical cultures was tested (10); standard chemotherapeutics are typically less effective when tested in the spherical model, because of the decreased fraction of cycling cells in this system, the presence of hypoxic regions, or restricted diffusion of the drug into the core of the spheroid. However, while the activity of doxorubicin, cyclophosphamide, cisplatin, and paclitaxel was reduced in spherical cultures, the activity of bortezomib was identical in most prostate and ovarian cancer monolayer and spherical cultures. Hypoxia, in fact, seemed to augment the proapoptotic effect of bortezomib in vitro (11); myeloma, lung, or colon cells were more sensitive to bortezomib when the cells were grown under low-oxygen conditions than when they were grown at standard oxygen concentrations. In contrast to standard chemotherapeutics, cell killing by bortezomib may in fact be greatest in the non-proliferating, hypoxic core of the tumor.

Proteasome inhibitors may also have a role in combination with existing drugs potentially overcoming intrinsic, acquired, or induced chemoresistance. Although some studies have tested the activity of bortezomib in combination with radiation therapy [2], [12], [13] this review approaches the treatment of solid tumors with proteasome inhibitors (primarily bortezomib) with a focus on mechanisms that are related to chemoresistance.

Section snippets

Proteasome inhibition and intrinsic mechanisms of chemoresistance

Altered expression by mutation, overexpression, or constitutive activity of a number of proteins can confer resistance to chemotherapy. These proteins protect tumor cells from cell-cycle arrest or apoptosis, or abrogate the toxic effects of chemotherapy; activation, overexpression, or mutation of these proteins is often a stage in transformation, and these proteins may in fact be required for the survival and proliferation of the tumor.

Proteasome inhibition and inducible mechanisms of chemoresistance

Tumor cells can avert chemotherapy-induced apoptosis through the activation of survival factors following chemotherapy or by the down-regulation of drug targets. Once again, NF-κB has been identified as a key mediator of inducible chemotherapy resistance; however, evidence exists for a role for Bcl-2 up-regulation or topoisomerase IIα down-regulation in chemoresistance.

Metabolic mechanisms contributing to the action of proteasome inhibitors

In several cases, proteasome-mediated protein degradation intersects pathways tied to a drug’s mechanism of action. Thus, the possibility exists that combination of a proteasome inhibitor with specific drugs could lead to synergistic activity.

Conclusion

Bortezomib has demonstrated activity in preclinical models of breast, prostate, pancreatic, colon, head and neck, and ovarian cancer. One of the most promising results of these experiments is the finding that proteasome inhibition can bypass mechanisms that lead to chemoresistance or can act as a mechanism for resensitizing cells to chemotherapy. Phase I and II trials that will test bortezomib in combination with agents that have shown activity preclinically (gemcitabine, CPT-11, and taxanes,

Acknowledgements

The author appreciates the expert assistance of Karen Oberheim in the preparation of this manuscript.

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