Although, by definition, cancer cells have a deregulated cell cycle, tumors often retain an intact G1 cell cycle checkpoint response via p53-dependent transactivation of p21, which then inhibits cyclin-dependent kinases (Cdk) and prevents G1/S transition. More importantly, tumors retaining this checkpoint response are also sensitive to therapeutic agents. Indeed, a strong positive correlation exists between the ability of tumor cells to arrest in G1 and sensitivity to platinum-based agents (cisplatin, tetraplatin and oxaliplatin) in the NCI 60- cell line tumor panel. This is also consistent with the finding that mutant-p53 tumor cells transfected with a p21 expression vector are sensitized to cisplatin. Moreover, our preliminary data demonstrate that p21- knockout induces resistance to cisplatin and to a novel analog DAP, which was designed to circumvent cisplatin resistance. The analog DAP is highly interesting among DNA-damaging agents in that it only inhibits G1-phase Cdk to selectively induce G1 arrest, and this consolidates the relationship between G1-phase Cdk inhibition by p21 and cell death. However, the underlying basis for this relationship has not been clearly defined in the literature, possibly due to signaling interference from the cross talk caused by inhibition of Cdk in S- and G2-phases, which are linked to cell-survival signaling. The availability of DAP, which does not inhibit the Cdk in these two phases, provides an important and timely opportunity to delineate this relationship so that rational approaches could emerge to improve the spectrum of therapeutic response. In preliminary studies, we have made a seminal observation that G1-phase Cdk complexes inhibited by DAP-induced p21 are substantially larger in size than the corresponding active complexes in control cells. Proteomic analysis of the inhibited complex identified the expected p21, but revealed PCNA as a novel recruit, which potentially links inhibition of G1-phase Cdk activity to platinum-mediated cell death. Therefore, we hypothesize that tumor cell death by platinum-based agents is dependent on p21 function at the G1-phase Cdk locus and this is facilitated by PCNA recruitment. We will address this hypothesis with three specific aims, which will better define our understanding of the process of G1-phase inhibition, and link this p21-dependent event to cell death. Moreover, comparative studies with platinum complexes will allow us to appreciate a mechanism of cisplatin resistance that is circumventable by non-cross-resistant analogs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127263-05
Application #
8033774
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Wolpert, Mary K
Project Start
2007-05-01
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2011
Total Cost
$255,440
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Eric S; Tang, XiMing; Peterson, Derick R et al. (2014) Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. Lung Cancer 85:88-93
He, G; Kuang, J; Koomen, J et al. (2013) Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents. Br J Cancer 109:2378-88
Preihs, Christian; Arambula, Jonathan F; Magda, Darren et al. (2013) Recent developments in texaphyrin chemistry and drug discovery. Inorg Chem 52:12184-92
Kim, Eric S; Lee, J Jack; He, Guangan et al. (2012) Tissue platinum concentration and tumor response in non-small-cell lung cancer. J Clin Oncol 30:3345-52
Arambula, Jonathan F; Sessler, Jonathan L; Siddik, Zahid H (2012) A texaphyrin-oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells. Medchemcomm 3:1275-1281
Martinez-Rivera, Michelle; Siddik, Zahid H (2012) Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem Pharmacol 83:1049-62
Arambula, Jonathan F; Sessler, Jonathan L; Siddik, Zahid H (2011) Overcoming biochemical pharmacologic mechanisms of platinum resistance with a texaphyrin-platinum conjugate. Bioorg Med Chem Lett 21:1701-5
He, Guangan; Kuang, Jian; Khokhar, Abdul R et al. (2011) The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog. Gynecol Oncol 122:402-9
Kurokawa, Tetsuji; He, Guangan; Siddik, Zahid H (2010) Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner. Cancer Chemother Pharmacol 65:427-36
Rowe, R Wanda; Strebel, Frederick R; Proett, Jesse M et al. (2010) Fever-range whole body thermotherapy combined with oxaliplatin: a curative regimen in a pre-clinical breast cancer model. Int J Hyperthermia 26:565-76

Showing the most recent 10 out of 12 publications