Human chorionic gonadotropin (hCG) interacts with lovastatin and ionizing radiation to modulate prostate cancer cell viability in vivo

Abstract

The ability of human chorionic gonadotropin (hCG) to modify prostate carcinoma viability in vitro and in vivo when combined with the HMG CoA reductase inhibitor lovastatin and ionizing radiation was investigated. Treatment of PC-3 cells in vitro with hCG caused a modest increase in numbers of non-viable cells within 96 h. Treatment of cells with hCG followed by exposure to the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The cytotoxic effects of hCG were blocked by expression of BCL-XL and dominant negative caspase 9. Treatment of mice bearing PC-3 flank tumors with lovastatin and hCG significantly reduced tumor volume within 7 days; this was also reflected in decreased ex vivo colony survival of the cells which correlated with increased cleavage of pro-caspase 3 and reduced Ki67 immuno-reactivity. In vitro, treatment of PC-3 cells with hCG followed by exposure to ionizing radiation enhanced the cytotoxic effects of hCG, that was further enhanced by lovastatin. In vivo, hCG radiosensitized PC-3 tumors and significantly enhanced the lethality of hCG and lovastatin treatment. Collectively, our findings argue that treatment of PC-3 prostate cancer tumors with hCG, lovastatin and radiation represents a potential novel therapeutic approach.

The flip side of doxorubicin

“…The increase in IL-6 plasma concentrations following doxorubicin treatment is reminiscent of other studies showing that ionizing radiation can cause the release of growth factors into the media/patient plasma e.g., TGFα 10 . IL-6, like TGFα, is a potent mediator of tumor cell growth and the fact that doxorubicin increases plasma IL-6 levels will be counter-productive to achieving a PR or CR in a patient using this drug, particularly a liver cancer patient 11 .…”

The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib

“… 9 RAS proteins, to be active and plasma membrane localized, are prenylated, and this essential modification can be targeted using specific farnesyl-transferase inhibitors or inhibitors of HMG CoA reductase (Statins). 10 However, K-RAS and N-RAS proteins, in addition to farnesylation, can also be alternatively geranyl geranylated. As a result, farnesyl transferase inhibitors have largely been unsuccessful in the clinic at controlling RAS-dependent tumors.…”

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

“…Mutated RAS proteins have been considered for several decades to be one of the most important cancerdriving proteins to therapeutically target (McCormick, 2015). RAS proteins, to be active and plasma membrane localized, are prenylated, and this essential modification can be targeted using specific farnesyl transferase inhibitors or inhibitors of HMG CoA reductase (i.e., statins) (Hamed et al, 2008). However, K-RAS and N-RAS proteins, in addition to farnesylation, can also be alternatively geranyl geranylated.…”