One aspect of conventional chemotherapy that often results in failure is the development of drug resistance through increased efficiency by the cancer cell in pumping drugs out of the cell, which is an energy requiring process. Many cancer cells, including breast cancer cells, have converted to aerobic glycolysis as the main source of ATP energy, suggesting that selective interference with glycolytic production of ATP in cancer cells may render these cells less able to pump out chemotherapeutic drugs. Many tumors selectively up-regulate the expression of lactate dehydrogenase A4 (LDH-A). This leads to the HYPOTHESIS: Selective LDH-A inhibitors will provide an ATP-depleting strategy to sensitize breast cancer cells to adjuvant chemotherapy.
SPECIFIC AIM : The applicant proposes to carry out an animal study of the effectiveness of inhibitors of human lactate dehydrogenase A4 (LDH-A) as sensitizers of conventional adjuvant cancer chemotherapy against breast cancer. The compounds that will be tested include the natural product gossypol, gossypol derivatives such as gossylic lactone and gossypol analogs, all of which are inhibitors of LDH-A. The phase 1 goals of this study are: 1) to demonstrate that treatment of the murine EMT- 6 mammary carcinoma cell with the above compounds decreases ATP production in vitro; and 2) to use this cell which is syngeneic to the Balb/c mouse as a mammary carcinoma tumor model to investigate tumor growth delay as an in vivo proof of principal that inhibition of ATP production will increase the sensitivity of tumor growth to standard chemotherapy with cyclophosphomide and 5-fluorouracil. Breast cancer remains the most common non-cutaneous cancer among US women. The most common treatments, either mastectomy or breast-conserving surgery combined with radiation, are often followed by systemic adjuvant therapies such as adjuvant hormone therapy or adjuvant chemotherapy to aid in prevention of recurrence. The goal of radiation or chemotherapy is to kill cancer cells with as much selectivity as possible. Cancer cells often become resistant to chemotherapy by pumping the drugs out of the cell, which requires energy. The question is whether cancer cells can be made more sensitive to existing drugs, which would extend the use of available therapies. Since most cancer cells have switched to glycolysis for energy production, cancer cells should be especially sensitive to inhibition of glycolysis. This research project will test whether compounds that are known to inhibit glycolysis will sensitize breast cancer cells to treatment with widely used chemotherapeutic drugs. The research will utilize an accepted animal model of mammary cancer to address this question. ? ? ?
