Skip to main content
main-content

01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Nitesh P Shirsath, Sonal M Manohar, Kalpana S Joshi
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-77) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

KJ conceptualized and guided the research project. NS performed experiments viz. cytotoxicity, flow cytometry, in vivo efficacy including PKPD studies and combination studies. SM performed and analyzed western blot, RT-PCR and siRNA experiments. Manuscript was written by NS and KJ. All authors approved the final manuscript.

Abstract

Background

Mantle cell lymphoma (MCL) is a well-defined aggressive lymphoid neoplasm characterized by proliferation of mature B-lymphocytes that have a remarkable tendency to disseminate. This tumor is considered as one of the most aggressive lymphoid neoplasms with poor responses to conventional chemotherapy and relatively short survival. Since cyclin D1 and cell cycle control appears as a natural target, small-molecule inhibitors of cyclin-dependent kinases (Cdks) and cyclins may play important role in the therapy of this disorder. We explored P276-00, a novel selective potent Cdk4-D1, Cdk1-B and Cdk9-T1 inhibitor discovered by us against MCL and elucidated its potential mechanism of action.

Methods

The cytotoxic effect of P276-00 in three human MCL cell lines was evaluated in vitro. The effect of P276-00 on the regulation of cell cycle, apoptosis and transcription was assessed, which are implied in the pathogenesis of MCL. Flow cytometry, western blot, immunoflourescence and siRNA studies were performed. The in vivo efficacy and effect on survival of P276-00 was evaluated in a Jeko-1 xenograft model developed in SCID mice. PK/PD analysis of tumors were performed using LC-MS and western blot analysis.

Results

P276-00 showed a potent cytotoxic effect against MCL cell lines. Mechanistic studies confirmed down regulation of cell cycle regulatory proteins with apoptosis. P276-00 causes time and dose dependent increase in the sub G1 population as early as from 24 h. Reverse transcription PCR studies provide evidence that P276-00 treatment down regulated transcription of antiapoptotic protein Mcl-1 which is a potential pathogenic protein for MCL. Most importantly, in vivo studies have revealed significant efficacy as a single agent with increased survival period compared to vehicle treated. Further, preliminary combination studies of P276-00 with doxorubicin and bortezomib showed in vitro synergism.

Conclusion

Our studies thus provide evidence and rational that P276-00 alone or in combination is a potential therapeutic molecule to improve patients’ outcome in mantle cell lymphoma.
Zusatzmaterial
Authors’ original file for figure 1
12943_2012_1074_MOESM1_ESM.pdf
Authors’ original file for figure 2
12943_2012_1074_MOESM2_ESM.gif
Authors’ original file for figure 3
12943_2012_1074_MOESM3_ESM.gif
Authors’ original file for figure 4
12943_2012_1074_MOESM4_ESM.gif
Authors’ original file for figure 5
12943_2012_1074_MOESM5_ESM.pdf
Authors’ original file for figure 6
12943_2012_1074_MOESM6_ESM.gif
Authors’ original file for figure 7
12943_2012_1074_MOESM7_ESM.gif
Authors’ original file for figure 8
12943_2012_1074_MOESM8_ESM.doc
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2012

Molecular Cancer 1/2012 Zur Ausgabe

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise