The novel retinoid AHPN/CD437 induces a rapid but incomplete apoptotic response in human myeloma cells

Joseph, Bertrand; Marchetti, Philippe; Lefebvre, O.; Schraen, Susanna; Méreau-Richard, Claude; Formstecher, Pierre

doi:10.1016/s0167-4889(02)00399-3

Cited by 6 publications

(9 citation statements)

References 15 publications

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“…These results were consistent with previous investigations showing that ATRA treatment induced potent inhibition on OPM-2 MM cell growth, 44,45 but no significant effects on U266 and L363 cells, which were detected as RAR␣2 Ϫ cells in our study. 46 Based on these observations, we conclude that RAR␣2 expression played a crucial role in mediating ATRAinduced MM cell death and growth inhibition.In this study, we found that RAR␣2 expression was highly related to poor prognosis in TT2 and TT3 clinical trials. Nonetheless, our previous investigation reported 70 high-risk genes in MM in which RAR␣2 was not included.…”

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confidence: 67%

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confidence: 67%

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RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Wang

Tricot

Shi

et al. 2009

Blood

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IntroductionMultiple myeloma (MM) is a plasma cell malignancy. 1,2 Although high-dose therapy and tandem bone marrow autotransplantation can produce higher response rates and longer survival than standard chemotherapy, MM remains largely incurable by current therapeutic strategies. 3,4 Furthermore, clinical outcomes of patients with MM are extremely heterogeneous, with survival ranging from only a few months to more than 15 years. [4][5][6] Increasing evidence suggests that genetic heterogeneity in MM cells largely accounts for the divergent clinical outcomes. 6 We have been pursuing the genetic characteristics of MM for nearly 10 years, which has contributed to the classification of MM diseases. [7][8][9][10][11] However, it remains unknown how to transform MM into a curable disease. Therefore, identification of new targets and genetic alterations, especially those for which there are available drugs, is important.All-trans retinoic acid (ATRA)-based regimens have been used in the therapy of acute promyelocytic leukemia (APL) for more than 20 years and have dramatically raised the 5-year disease-free survival to more than 70%. Furthermore, the toxicity of ATRA has been limited compared with conventional cytotoxic chemotherapy. 12 The high efficacy of retinoic acid (RA)-based therapy in APL and its well-documented safety profile have stimulated considerable interests in the treatment of other malignancies, [13][14][15] including myeloma. 16,17 Despite many efforts, however, clinical benefits of ATRA treatment in other tumors have been minor. RAR␣ has 2 major isoforms, RAR␣1 and RAR␣2, which differ in their expression patterns and N-terminal AF-1 functional domains. 18 Both RAR␣1 and RAR␣2 are considered specific receptors for RA-based reagents. However, the specific cellular roles of RAR␣1 and RAR␣2 are still unclear. In this study, we found that RAR␣2 plays a crucial role in myeloma progression, and more importantly, in mediating RA-based therapy of RAR␣2 ϩ MM diseases. Methods Study subjectsCD138 ϩ myeloma cell samples were obtained from patients who were enrolled on the National Institutes of Health (NIH)-sponsored clinical trials UARK 98-026 (Total Therapy 2 [TT2]) and UARK 03-033 (TT3). The Institutional Review Board of the University of Arkansas for Medical Sciences approved the research studies, and all subjects provided written informed consent in accordance with the Declaration of Helsinki.We have an inventory of more than 30 myeloma cell lines in our laboratory. Cells from these cell lines were cultured in RPMI 1640 containing 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine (Gibco), penicillin (100 U/mL), and streptomycin (100 g/mL) in a humidified incubator at 37°C in 5% CO 2 . Gene expression profilingPlasma cell purifications and gene expression profiling, using the Affymetrix U133Plus2.0 microarray, were performed as previously described. 9,11 Signal intensities were preprocessed and normalized by GCOS1.1 software (Affymetrix). 9,11 Myeloma cell samples from 80 newly diagnosed patien...

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confidence: 67%

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confidence: 67%

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Wang

Tricot

Shi

et al. 2009

Blood

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“…Preclinical development In vitro and in vivo, in different models of Synthetic retinoid (triterpenoid) able to promote human tumors. [73][74][75] MOMP independently from nuclear receptors. [76][77][78] CDDO Phase I clinical trials Metastatic or unresectable solid tumors Synthetic retinoid (triterpenoid), induces and lymphoma MOMP in isolated mitochondria.…”

Section: Cd437mentioning

confidence: 99%

Targeting p53 to mitochondria for cancer therapy

Galluzzi

Morselli²,

Kepp³

et al. 2008

Cell Cycle

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Although the tumor suppressor protein p53 is a major senescence- and cell death-inducing transcription factor, recent work has clearly demonstrated that p53 has additional, extranuclear effects that contribute to its cell cycle-arresting and proapoptotic functions. Mitochondrial outer membrane permeabilization (MOMP) is (one of) the most prominent apoptotic checkpoint(s), and cytoplasmic p53 can induce MOMP by direct interactions with multidomain proteins from the Bcl-2 family present at the mitochondrial outer membrane (OM). Since MOMP is commonly disabled in cancer cells, its pharmacological induction constitutes a therapeutic goal, and this has stimulated the design of mitochondriotropic inducers of apoptosis, both inhibitors of antiapoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL) or activators of their proapoptotic counterparts (e.g., Bak, Bax). Moreover, novel approaches of gene therapy have been designed in which p53 is specifically targeted to mitochondria and have been demonstrated to inhibit the growth of human cancer xenografts in immunodeficient mice. Thus, a number of distinct strategies can be employed to achieve the therapeutic induction of MOMP in cancer cells.

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“…Moreover, the treatment of human malignant melanoma with combined p53 vector plus antisense cyclin D1 has been observed to lead to enhanced growth-suppressive and apoptotic effects as compared with either therapy alone [173]. In this matter, it has also been reported that diverse anticancer drugs, including Mimeault/Bonenfant/Batra doxorubicin, vinblastine, paclitaxel, cytosine arabinoside, betulinic acid and the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), are able to induce apoptotic death of melanoma cells via a mitochondrion-dependent pathway leading to the activation of caspases [166,183]. This suggests that the compounds which are able to alter mitochondrial functions could represent interesting adjuvant antitumoral agents against metastatic melanoma forms.…”

Section: Combination Therapiesmentioning

confidence: 99%

New Advances on the Functions of Epidermal Growth Factor Receptor and Ceramides in Skin Cell Differentiation, Disorders and Cancers

Mimeault

Bonenfant

Batra

2004

Skin Pharmacol Physiol

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Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed. The alterations in EGFR signaling and ceramide metabolism, which might be involved in the etiopathogenesis of diverse skin disorders and cancers, are described. New progress in understanding of skin organization, which might provide the basis for the design of new transcutaneous drug delivery techniques as well as for the development of new therapies of skin disorders and cancers, are reported.

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The novel retinoid AHPN/CD437 induces a rapid but incomplete apoptotic response in human myeloma cells

Cited by 6 publications

References 15 publications

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Targeting p53 to mitochondria for cancer therapy

New Advances on the Functions of Epidermal Growth Factor Receptor and Ceramides in Skin Cell Differentiation, Disorders and Cancers

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