Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression.
Proapoptotic drugs such as docetaxel displayed least toxicity and highest antitumor efficacy following dosing during the circadian rest phase in mice, suggesting that cell cycle and apoptotic processes could be regulated by the circadian clock. In study 1, mouse bone marrow and/or tumor were obtained every 4 h for 24 h in C3H/HeN mice with or without MA13/C mammary adenocarcinoma in order to determine the circadian patterns in cell-cycle phase distribution and BCL-2 anti-apoptotic protein expression. In study 2, mouse bone marrow from B6D2F1 mice was sampled every 3 h for 24 h in order to confirm the BCL-2 rhythm and to study its relation with 24 h changes in the expression of proapoptotic BCL-2-associated X protein (BAX) protein and clock genes mPer2, mBmal1, mClock, and mTim mRNAs. The rhythms in G1-, S- or G2/M-phase cells were shifted in tumor compared with bone marrow. In the tumor, the mean proportion of G2/M-phase cells increased by 75% from late rest to late activity span (P from cosinor = 0.001). No 24 h rhythm was found for BCL-2 in tumors. In contrast to this, in the bone marrow, mean BCL-2 expression varied 2.8-fold in B6D2F1 mice (P=0.025) and 3- or 4.5-fold in tumor-bearing and nontumor-bearing C3H/HeN mice, with a peak during the early rest span (P=0.024 and P<0.001, respectively). BAX varied fivefold during the 24 h span with a major peak occurring near mid-activity (P=0.007). The mean mRNAs of mPer2, mClock, and mBmal1 varied twofold to threefold over the 24 h, with high values during the activity span (P<0.05). In the tumor, the circadian organization in cell-cycle phase distribution was shifted and BCL2 rhythm was ablated. Conversely, a molecular circadian clock likely regulated BCL-2 and BAX expression in the bone marrow, increasing cellular protection against apoptosis during the rest span.
Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3K␣. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.The phosphoinositide 3-kinase (PI3K) 4 /Akt pathway is activated in a variety of solid and non-solid tumors (1) and therefore is considered as a potential intervention point for anticancer therapeutics. Activation of the pathway is frequently caused by mutations in PI3K␣ that enhance its catalytic activity, leading to the generation of phosphatidyl 3,4,5-trisphosphate (PIP3) (2) or by mutations or deletions in the tumor suppressor PTEN (phosphatase and tensin homolog) that result in its loss of function. PTEN antagonizes the activity of PI3K␣ through the dephosphorylation PIP3 (3). In addition, PI3K␣ can be activated by mutations in certain receptor-tyrosine kinases as well as by mutations in the oncogene KRAS (4, 5).The PIP3 generated by activation of PI3K␣ or sustained by the inactivation of PTEN binds to a subset of lipid-binding domains in downstream targets such as the pleckstrin homology (PH) domain of the oncogene Akt (6, 7); thereby, recruiting it to the plasma membrane. Once at the plasma membrane, Akt can be activated (8, 9). When active, Akt phosphorylates several effector molecules including the Forkhead box O (FOXO) transcription factors (10, 11). FOXO proteins are a family of conserved polypeptides that bind to DNA as a monomer and activate the transcription of genes that are involved in numerous biologically relevant processes such as metabolism, differentiation, proliferation, longevity, and apoptosis (12, 13). Akt phosphorylates FOXO proteins at three conserved consensus sites, which leads to conformational changes that facilitate CRM-1-mediated nuclear export (14, 15). Nuclear FOXO proteins function as regulators of transcription, whereas cytoplasmic FOXO proteins are considered inactive. It is well established that FOXO is negatively regulated by various proliferative and antiapoptotic signaling pathways that activate the PI3K/Akt signaling cascade (11). Therefore, we chose to employ a high content imaging approach to monitor the nucleocytoplasmic translocation of a GFP-FOXO3a fusion protein in U2OS cells (U2foxRELOC) (16,17) as the readout for biological inhibition...
The relevance of circadian rhythms in irinotecan and oxaliplatin tolerability was investigated with regard to antitumour activity. Mice bearing Glasgow osteosarcoma (GOS) received single agent irinotecan (50 or 60 mg kg 71 per day) or oxaliplatin (4 or 5.25 mg kg 71 per day) at one of six dosing times expressed in hours after light onset (3, 7, 11, 15, 19 or 23 hours after light onset). Irinotecan (50 mg kg 71 per day) and oxaliplatin (4 or 5.25 mg kg 71 per day) were given 1 min apart at 7 or 15 hours after light onset, or at their respective times of best tolerability (7 hours after light onset for irinotecan and 15 hours after light onset for oxaliplatin) or worst tolerability (15 hours after light onset for irinotecan and 7 hours after light onset for oxaliplatin). Tumour growth rate was nearly halved and per cent increase in estimated life span (% ILS) was -doubled in the mice receiving irinotecan at 7 hours after light onset as compared to 15 hours after light onset (P50.05). Results of similar magnitude were obtained with oxaliplatin for both endpoints, yet with 7 hours after light onset corresponding to least efficacy and 15 hours after light onset to best efficacy (P50.05). Irinotecan addition to oxaliplatin proved therapeutic benefit only if the schedule consisted of irinotecan administration at 7 hours after light onset and oxaliplatin delivery at 15 hours after light onset, i.e. when both drugs were given near their respective 'best' circadian times. These would correspond to the middle of the night for irinotecan and the middle of the day for oxaliplatin in humans.
. Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice. Am J Physiol Regul Integr Comp Physiol 287: R844 -R851, 2004. First published June 24, 2004 10.1152/ajpregu. 00085.2004.-Rest-activity or cortisol rhythms can be altered in cancer patients, a condition that may impair the benefits from a timed delivery of anticancer treatments. In rodents, the circadian pattern in rest-activity is suppressed by the destruction of the suprachiasmatic nuclei (SCN) in the hypothalamus. We sought whether such ablation would result in a similar alteration of cellular rhythms known to be relevant for anticancer drug chronopharmacology. The SCN of 77 B6D2F1 mice synchronized with 12 h of light and 12 h of darkness were destroyed by electrocoagulation [SCN(Ϫ)], while 34 animals were sham operated. Activity and body temperature were recorded by telemetry. Blood and organs were sampled at one of six circadian times for determinations of serum corticosterone concentration, blood leukocyte count, reduced glutathione (GSH), and dihydropyrimidine dehydrogenase (DPD) mRNA expression in liver and cell cycle phase distribution of bone marrow cells. Sham-operated mice displayed significant 24-h rhythms in rest-activity and body temperature, whereas such rhythms were found in none and in 15% of the SCN(Ϫ) mice, respectively. SCN lesions markedly altered the rhythmic patterns in serum corticosterone and liver GSH, which became nonsinusoidal. Liver DPD mRNA expression and bone marrow cell cycle phase distribution displayed similar 24-h sinusoidal patterns in shamoperated and SCN(Ϫ) mice. These results support the existence of another light-dark entrainable pacemaker that can coordinate cellular functions in peripheral organs. They suggest that the delivery of anticancer treatments at an optimal time of day may still be beneficial, despite suppressed rest-activity or cortisol rhythms. circadian coordination; cancer chronotherapeutics; cortisol; cell cycle; dihydropyrimidine dehydrogenase APPROXIMATELY 25% of cancer patients displayed profound alterations of rest-activity pattern and cortisol rhythm independently of tumor stage or general condition (32-34). Poorer tumor response and shorter survival were reported in these patients compared with those with near normal circadian function (36,43). Such altered circadian function could also impair the therapeutic benefit that can result from chronotherapeutics, i.e., the delivery of anticancer treatments at selected times of day (12,23,26,27).This treatment optimization method is based on the regulation of cellular metabolism and proliferation by a molecular clock. This clock consists of interconnected molecular loops involving up to 12 specific clock genes. It has been uncovered in most mammalian tissues (21,35,41,42) and rhythmically regulates the transcription of 5-10% of the genome (14,21,41,42). Indeed, sustained rhythms in transcription or other cellular functions have been demonstrated in cultured mammalian cells, giving rise to the con...
Experimental tumor models constitute a prerequisite toward chronotherapy testing in cancer patients. Studies in experimental models are required to understand the relation between tumor rhythms and antitumor treatments efficacy. In healthy tissues, cell proliferation, and differentiation processes are regulated precisely and exhibit marked circadian rhythmicity. Experimental and human tumors can retain circadian rhythms or display altered oscillations. Healthy tissues can also display rhythm modifications, possibly related to cancer stage. Cellular rhythms modulate the metabolism of cytotoxic agents and the cellular response to them; hence, they determine the chronopharmacology of anticancer drugs. Circadian rhythms in host tolerability and/or cancer chemotherapy efficacy have been demonstrated with nontoxic doses of drugs in several experimental tumor models, while in other ones a circadian-time effect was only seen within a specific dose range. The usual coupling between tolerability and efficacy rhythms of anticancer agents has resulted in significant improvement of their therapeutic index. Results of laboratory animal studies have been extrapolated to the design of clinical cancer therapy trials involving a chronobiological approach.
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