Axel H. Schönthal , Ph.D.

Research Interests

Cancer cells are different from normal cells in that they grow indefinitely and eventually form a tumor in the body. We study the molecular processes that are altered in cancer cells in order to attack them with novel anti-cancer molecules. In addition, we investigate whether we can prevent the development of tumor growth by treatment of cells with various combinations of anti-cancer compounds.

For example, we have been studying the drug celecoxib, which is a selective inhibitor of cyclooxygenase-2 (COX-2). (Celecoxib is the active ingredient in the prescription drug CELEBREX). Results from our lab and others have indicated that this drug might be useful for tumor therapy. Intriguingly, however, it appears that the COX-2 inhibitory function of celecoxib is not required for its anti-tumor effects. For example, we have synthesized a derivative of celecoxib, called dimethyl-celecoxib (DMC), that has lost the ability to inhibit the COX-2 enzyme. Amazingly, though, DMC is even more potent than its parent compound celecoxib in inhibiting tumor growth in vitro and in vivo! Therefore, the question arises: Since DMC cannot possibly work via the inhibition of COX-2, what is the mechanism by which this drug suppresses tumor growth?

The question as to the underlying molecular mechanism(s) of DMC's anti-cancer effect is very important, also because the answer will direct us towards the inclusion of other drugs that might complement, and therefore enhance, the overall anti-tumor response.

A lot of our work is done in close collaboration with two other laboratories, Dr. Hofman's and Dr. Chen's, and together we form the interdisciplinary core of the Glioma Research Group. Every week, we have a joint lab meeting for all members, so that everybody is exposed to and updated on the progress of all three laboratories (to better endure this two-hour meeting, nutritional support in form of bagels and low-fat cream cheese is being provided).

Dr. Hofman's lab works on tumor angiogenesis, and our common goal is to determine whether DMC can work as an anti-angiogenic agent, i.e., whether DMC can attack tumors via the killing of the tumor's blood supply.

Dr. Chen is a neurosurgeon that operates on patients with brain cancers; therefore, he has access to primary tumor samples, from which his lab isolates cancer stem cells; together, we investigate whether DMC is able to effectively destroy brain cancer stem cells.

Degrees

University Of Karlsruhe, PHD, 1988
University Of Karlsruhe, MS, 1984

Fellowships

Univeristy of California, San Diego, Cancer Center, 1988 - 1991

S. Mueller, E. Cadenas, A.H. Schönthal. 2000. Regulation of HCT116 colon carcinoma cell-cell adhesion by p21(Waf1). Cancer Res. 60, 156-163.

R.C.Wu, X. Li, A.H. Schönthal. 2000. Transcriptional activation of p21(Waf1) by PTEN/MMAC tumor suppressor phosphatase. Mol. Cell. Biochem. 203, 59-71.

A.H. Schönthal. 2001. Role of protein phosphatase 2A in cancer. Cancer Lett. 170, 1-13.

T.C. Chen, P. Wadsten, S. Su, N. Rawlinson, F.M. Hofman, C. Hill, A.H. Schönthal. 2002. The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21Cip1 and p27Kip1, resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. Cancer Biol. Therapy 1, 268-276.

H. Zhou, M. Luo, A.H. Schönthal, M. Pike, M. Stallcup, W. Zheng, L. Dubeau. 2002. Regulation of ovarian epithelial tumor growth by menstrual cycle hormones. Cancer Biol. Therapy 1, 300-306.

R.C. Wu, X. Li, A.H. Schönthal. 2002. Loss of cellular adhesion to matrix induces p53-independent expression of PTEN tumor suppressor. BMC Mol. Biol. 3, 11.

Schönthal AH. - Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy. - Br J Cancer [ 2007 ] Oct 23.

Pyrko P, Schönthal AH, Hofman FM, Chen TC, Lee AS. - The Unfolded Protein Response Regulator GRP78/BiP as a Novel Target for Increasing Chemosensitivity in Malignant Gliomas. - Cancer Res [ 2007 ] Oct 15;67(20):9809-9816

Pyrko P, Kardosh A, Schönthal AH. - Celecoxib transiently inhibits cellular protein synthesis. - Biochem Pharmacol [ 2007 ] Sep 1.

Chen S, Liu X, Yue P, Schönthal AH, Khuri FR, Sun SY. - CHOP-dependent DR5 induction and ubiquitin/proteasome-mediated c-FLIP downregulation contribute to enhancement of TRAIL-induced apoptosis by dimethyl-celecoxib in human non-small cell lung cancer cells. - Mol Pharmacol [ 2007 ] Aug 7.


Schönthal AH. - Induction of apoptosis by celecoxib in cell culture: an uncertain role for cyclooxygenase-2. - Cancer Res [ 2007 ] Jun 1;67(11):5575-6; author reply 5576 .

Kardosh A, Soriano N, Pyrko P, Liu YT, Jabbour M, Hofman FM, Schönthal AH. - Reduced survivin expression and tumor cell survival during chronic hypoxia and further cytotoxic enhancement by the cyclooxygenase-2