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Letters to the Editor |
. Cancer Res., 61: 7552–7555, 2001.1
Laboratory of Molecular Biology, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche "Mario Negri", via Eritrea, 62, 20157 Milan, Italy
Letter
The retinoid 6-[-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437) is the prototype of a new class of promising anticancer agents endowed with strong and selective apoptogenic properties against different types of neoplastic cells (1, 2, 3) . The compound is active on a variety of carcinoma (4, 5, 6) and leukemia (7 , 8) cell lines and demonstrates interesting in vivo activity on experimental models of acute myelogenous leukemia (9) , ovarian cancer (10) , and melanoma (11) . Although the molecular determinants underlying the pharmacological activity of CD437 are still a matter of speculation, the mechanism of action of the agent is independent of the activation of nuclear retinoic acid receptors of the RAR2 and retinoid X receptor subtypes (7 , 8 , 12) and is likely to be fundamentally different from that of classical retinoids and many chemotherapeutic agents of clinical significance (9) . Mitochondria (13) and membrane death receptors (14) are some of the potential molecular targets of CD437 in neoplastic cells, although the predominant mechanism of action of the agent is likely to be different in different cellular contexts.
In a recent issue of Cancer Research, Kumar et al. (15)
demonstrated that the ovarian carcinoma cell line 2008 is sensitive to the antiproliferative and cytotoxic action of CD437. By contrast, the two derived sublines made resistant to paclitaxel, 2008/13/4 and 2008/13/7, are cross-resistant to CD437. The resistance index is 250 for paclitaxel and 6–7 in the case of CD437. Cross-resistance is unrelated to overexpression of RAR-
in the two cell lines refractory to taxanes. The authors suggested that one or more common determinant(s) of cellular sensitivity to paclitaxel and CD437 is altered in the two cell lines. With respect to this, the authors discussed the possibility that defective activation of p38 and/or JNK kinase activity by both paclitaxel and CD437 may play a role in the observed cross-resistance.
Before the publication of the article by Kumar et al. (15)
, we described the isolation of an acute promyelocytic leukemia-derived cell line made selectively resistant to CD437 by continuous passage in increasing concentrations of the agent (9)
. We demonstrated that the CD437-resistant cell line (NB4.437r) is approximately 60–70-fold more resistant to the retinoid than its parental counterpart (NB4; Ref. 9
). As shown in Fig. 1
, NB4.437r cells are completely resistant to CD437 (1 µM) both in terms of growth inhibition and apoptotic response. Moreover, whereas the number of NB4 viable cells is decreased in a dose-dependent manner after treatment with CD2325 and a number of other biologically active CD437 structural analogues,3
a similar effect is not observed in the case of NB4.437r cells, which maintain their viability even upon challenge with the retinoids at 10 µM. CD437- and CD2325-dependent cytotoxicity in NB4 cells is the result of a classical apoptogenic effect, which results in nuclear fragmentation and activation of terminal caspases (Ref. 7
; data not shown). Neither of these phenomena is observed in NB4.437r cells. The NB4 and NB4.437r myeloid blasts have very similar growth rates (9)
and the same karyotype (9)
and do not express significant amounts of RAR-.3
In addition, JNK is activated by CD437 to a similar extent in both NB4 and NB4.437r cells (9)
. Interestingly, NB4.437r cells are practically as sensitive as the NB4 parental line to the apoptogenic action of paclitaxel and a number of other chemotherapeutic agents (9)
. Thus, in a cellular model complementary to that described by Kumar et al. (15)
, we confirm that RAR- is not involved in resistance to CD437. In addition, our published results (9)
do not support a role for JNK in mediating the apoptogenic or cytotoxic effects of CD437. Finally, and more importantly, we demonstrate that resistance to CD437 is not necessarily associated with refractoriness to taxanes.
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ACKNOWLEDGMENTS
We thank CIRD-Galderma (Sophia Antipolis, France) and Indena SpA (Milan, Italy) for the kind gifts of CD437, CD2325, and paclitaxel, respectively. We are indebted to Prof. Silvio Garattini and Mario Salmona for critical reading of the letter.
FOOTNOTES
1 Supported in part by grants from the Associazione per la Ricerca contro il Cancro and the Weizmann-Pasteur-Mario Negri Foundation. 
2 The abbreviations used are: RAR, retinoic acid receptor; JNK, c-Jun NH2-terminal kinase.
Received 11/ 2/01. Accepted 1/29/02.
REFERENCES
. Cancer Res., 61: 7552-7555, 2001.. Cancer Res., 61: 7552–7555, 2001.1
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140
In our study (1)
, we demonstrated that two paclitaxel-resistant sublines derived from a human ovarian carcinoma cell line (2008) are cross-resistant to the synthetic retinoid CD437. We also demonstrated that neither the paclitaxel resistance nor the CD437 cross-resistance phenotype was associated with the observed overexpression of retinoic acid receptor in the paclitaxel-resistant sublines. Based on the similarity of the reported biochemical and cellular alterations induced by CD437 and paclitaxel (please refer to paragraph 9 of the "Results and Discussion" section of our article, Ref. 1
), we speculated that one or more common determinants of cellular sensitivity to these drugs may be altered in the paclitaxel-resistant sublines.
Drs. Garattini, Gianni’, and Terao in their letter (2) indicate that, based on the study of Ponzanelli et al. (3) , development of resistance to CD437 in the NB4.437r cells does not necessarily associate with cross-resistance to paclitaxel. This is in contrast to our observation (1) , and based on this, Garattini et al. (2) in their letter emphasize that sensitivity/resistance to CD437 is likely controlled by different determinants and molecular mechanisms in different neoplastic cell types and that care should be exercised in generalizing our observations (1) to cellular models other than the ovarian carcinoma. This is an important point of contention, albeit somewhat surprising considering that Garattini et al. (2) base their arguments on a single CD437-resistant cell line themselves. Nevertheless, it would be safe to assume that only those completely unfamiliar with experimental cancer therapeutic research would not exercise extreme caution before taking a giant leap of faith based on a single data point. Thus, we are at a loss as to the precise meaning of their comments. Garattini et al. (2) further suggest that it would be interesting to assess whether CD437/paclitaxel cross-resistance is a peculiarity of ovarian carcinoma cells. This suggestion has some merit, although in the same vein, we wonder whether lack of association of CD437 resistance with paclitaxel resistance in the NB4 cells might be a "peculiarity" of the acute promyelocytic leukemia-derived cell line.
Despite the foregoing, the comment of Garattini et al. that "it would be relevant to evaluate whether combinations of taxanes and CD437 letters to the editor or analogues have less than additive, additive, or synergistic effects to establish potential common intracellular pathways controlling the cytotoxic activity of the two agents" is well received. We are indeed in the process of analyzing the results obtained from such an experiment that would help shed some light on possible common pathways in the paclitaxel-resistant human ovarian carcinoma cell lines.
In addition, in our study (1) , we speculated that one of these common cellular determinants that control the response of the paclitaxel-resistant cells to both paclitaxel and CD437 might be p38 MAPK.1 This speculation was based on our observation of the lack of activation of p38 MAPK in response to paclitaxel treatment in the drug-resistant cells.2 In contrast [according to Garattini et al. (2) ], the study of Ponzanelli et al. (3) does not support a role for JNK in mediating the apoptogenic and/or cytotoxic effects of CD437 because CD437 activated JNK to a similar degree in the NB4 and CD437-resistant NB4.437r cells. We do not understand this comment, because we merely speculated on p38 MAPK as being a determinant [which Ponzanelli et al. (3) have unfortunately not investigated], not JNK.
Paclitaxel and retinoids are proving extremely beneficial in the chemotherapeutic treatment of ovarian tumors. The availability (now) of a CD437-resistant human ovarian carcinoma cell line provides us with an excellent opportunity to decipher the mechanism of CD437 resistance. Information obtained herein will hopefully provide insight into development of CD437 analogues that are able to overcome such acquired CD437 resistance in human ovarian tumors.
FOOTNOTES
The abbreviations used are: MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase.
Received 1/ 8/02. Accepted 1/29/02.
REFERENCES
. Cancer Res., 61: 7552-7555, 2001.
. Cancer Res., 61: 7552-7555, 2001.
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