Nuclear-cytoplasmic trafficking of
proteins is a significant factor in the development of
cancer and drug resistance. Subcellular localization of exported
proteins linked to
cancer development include those involved in cell growth and proliferation, apoptosis, cell cycle regulation, transformation, angiogenesis, cell adhesion, invasion, and
metastasis. Here, we examined the basic mechanisms involved in the export of
proteins from the nucleus to the cytoplasm. All
proteins over 40kDa use the nuclear pore complex to gain entry or exit from the nucleus, with the primary nuclear export molecule involved in these processes being chromosome region maintenance 1 (CRM1,
exportin 1 or XPO1).
Proteins exported from the nucleus must possess a hydrophobic
nuclear export signal (
NES) peptide that binds to a hydrophobic groove containing an active-site Cys528 in the
CRM1 protein. CRM1 inhibitors function largely by covalent modification of the active site Cys528 and prevent binding to the cargo
protein NES. In the absence of a CRM1 inhibitor, CRM1 binds cooperatively to the NES of the cargo
protein and RanGTP, forming a trimer that is actively transported out of the nucleus by facilitated diffusion. Nuclear export can be blocked by CRM1 inhibitors,
NES peptide inhibitors or by preventing post-translational modification of cargo
proteins. Clinical trials using the classic CRM1 inhibitor
leptomycin B proved too toxic for patients; however, a new generation of less toxic small molecule inhibitors is being used in clinical trials in patients with both
hematological malignancies and solid
tumors. Additional trials are being initiated using small-molecule CRM1 inhibitors in combination with chemotherapeutics such as
pegylated liposomal doxorubicin. In this review, we present evidence that combining the new CRM1 inhibitors with other classes of
therapeutics may prove effective in the treatment of
cancer. Potential combinatorial
therapies discussed include the use of CRM1 inhibitors and the addition of
alkylating agents (
melphalan),
anthracyclines (
doxorubicin and
daunomycin), BRAF inhibitors,
platinum drugs (
cisplatin and
oxaliplatin), proteosome inhibitors (
bortezomib and
carfilzomib), or
tyrosine-kinase inhibitors (
imatinib). Also, the sequence of treatment may be important for combination
therapy. We found that the most effective treatment regimen involved first priming the
cancer cells with the CRM1 inhibitor followed by
doxorubicin,
bortezomib,
carfilzomib, or
melphalan. This order sensitized both de novo and acquired
drug-resistant
cancer cell lines.