Current therapeutic uses of lenalidomide in multiple myeloma

Hideshima, Teru; Richardson, Paul G.; Anderson, Kenneth C.

doi:10.1517/13543784.15.2.171

Cited by 33 publications

(20 citation statements)

References 73 publications

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“…An arguably faster path to development is to reposition established drugs as anticancer agents. Successful examples of this approach include cyclooxygenase-2 inhibitors, which are FDA-approved anti-inflammatory drugs that are approved for cancer chemoprevention in familial adenomatous polyposis patients, and lenalidomide, an analogue of thalidomide, which was originally marketed for morning sickness that is now approved for therapy of myelodysplastic syndromes (24). Other approved drugs that are currently under investigation as anticancer agents include the oral hypoglycemic rosiglitazone, the immunosuppressant rapamycin, and the birth control hormone medroxyprogesterone acetate.…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo

Gills¹,

LoPiccolo²,

Tsurutani³

et al. 2007

Clinical Cancer Research

303

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Purpose: The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents. Experimental Design: HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non–small cell lung carcinoma (NSCLC) xenografts with biomarker assessment. Results: Three of six HIV protease inhibitors, nelfinavir, ritonavir, and saquinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 μmol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor–induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis. Conclusions: Nelfinavir is a lead HIV protease inhibitor with pleiotropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration–approved drug that could be repositioned as a cancer therapeutic.

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Section: Discussionmentioning

confidence: 99%

Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo

Gills¹,

LoPiccolo²,

Tsurutani³

et al. 2007

Clinical Cancer Research

303

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“…Moreover, recent data has suggested that immunomodulatory drugs can also favorably influence the activity of dendritic cells in this setting (56). The data supporting the immunomodulatory role of these agents, including thalidomide and lenalidomide, have been derived preclinically and now most recently clinically (10,57). Therefore, a combination therapy using 1D09C3 in association with immunomodulatory drugs might represent a compelling avenue.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ Enhances the Antimyeloma Activity of the Fully Human Anti–Human Leukocyte Antigen-DR Monoclonal Antibody 1D09C3

et al. 2007

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To investigate the therapeutic activity of the fully human anti-HLA-DR antibody 1D09C3 in multiple myeloma (MM), we reevaluated HLA-DR expression on CD138 + cells, analyzed the capacity of IFN-; to up-regulate HLA-DR expression on MM cell lines, and tested the in vitro and in vivo activity of 1D09C3 alone or in combination with IFN-;. CD138+ HLA-DR + cells were detected in 31 of 60 patients, with 15 of 60 patients having z20% CD138 + HLA-DR + cells (median, 50%; range, 23-100). Because primary plasma cells cannot be efficiently cultured in vitro, we used a panel of MM cell lines with a dim/ negative to bright HLA-DR expression to evaluate 1D09C3-induced cell death. Annexin V/propidium iodide (PI) staining showed that 1D09C3-induced cell death correlated with constitutive HLA-DR expression. Induction of HLA-DR by IFN-; restored the sensitivity of HLA-DR dim cell lines to 1D09C3. In vivo, the combined IFN-;/1D09C3 treatment significantly increased the median survival of nonobese diabetic/severe combined immunodeficient mice xenografted with KMS-11 cell line, compared with controls (147 versus 48 days, P V 0.0001) or mice receiving 1D09C3 alone (147 versus 92 days, P V 0.03). The better therapeutic activity of IFN-;/ 1D09C3 treatment over 1D09C3 alone was further shown by a 2-fold increase of mice being disease-free at 150 days after xenograft (47% versus 25%). No mice experienced any apparent treatment-related toxicity. Our data show that (a) one fourth of MM patients express HLA-DR on CD138 + cells and (b) IFN-;-induced up-regulation of HLA-DR results in a potent enhancement of the in vivo antimyeloma activity of 1D09C3. [Cancer Res 2007;67(7):3269-75]

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“…LEN appears to have direct and indirect effects, including the ability to inhibit cell growth and survival, induce apoptosis, inhibit adhesion to the host microenvironment, inhibit angiogenesis, and augment immune cell activity. 18 It has been hypothesized that some or all of these effects might also influence keratinocytes in patients receiving LEN and contribute to rash development. 8 As such, some authors attribute LEN-related rash to its direct antitumor effects, others to its indirect immunomodulatory effects.…”

Section: Physiology Of Len-related Rashmentioning

confidence: 99%