Antibiotics

Rich66 · 02-04-2010, 10:17 AM

(Doxy for bone mets, w/Zol, w/Cyclo, Tetra reverse Pac resistance)

Br J Cancer. 2007 May 21;96(10):1526-31. Epub 2007 Apr 17.
Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer.

FULL TEXT (free)

Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G.
Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2.
Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

PMID: 17437017 [PubMed - indexed for MEDLINE]

Toxicol Appl Pharmacol. 2005 Feb 1;202(3):268-77.
Doxycycline potentiates antitumor effect of cyclophosphamide in mice.

Chhipa RR, Singh S, Surve SV, Vijayakumar MV, Bhat MK.
National Centre for Cell Science, Pune University, Campus Ganeshkhind, NCCS Complex, Pune, Maharashtra, 411 007, India.
Cyclophosphamide (CPA) is a widely used chemotherapeutic drug in neoplasias. It is a DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms including breast cancer. The therapeutic effectiveness of CPA is limited by the high-dose hematopoietic, renal, and cardiac toxicity that accompanies the systemic distribution of liver-derived activated drug metabolites. The present study examines the potential of combining well-tolerated antibiotic doxycycline (DOX) with CPA and understanding the mechanism of cell killing. Interestingly, we found that DOX significantly enhances the tumor regression activity of CPA on xenograft mice model bearing MCF-7 cells. DOX also potentiates MCF-7 cell killing by CPA in vitro. In presence of DOX (3 microg/ml), the IC50 value of CPA decreased significantly from 10 to 2.5 mM. Additional analyses indicate that the tumor suppressor p53 and p53-regulated proapoptotic Bax were upregulated in vivo and in vitro following CPA treatment in combination with DOX, suggesting that upregulation of p53 may contribute to the enhancement of antitumor effect of CPA by DOX. Furthermore, downregulation of antiapoptotic Bcl-2 was observed in animals treated with CPA and CPA plus DOX when compared to untreated or DOX-treated groups. Our results raise the possibility that this combination chemotherapeutic regimen may lead to additional improvements in treatment of breast cancer.

PMID: 15667832 [PubMed - indexed for MEDLINE]

Results

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CPA is a cell cycle-dependent DNA and protein alkylating agent that has a broad spectrum of activity against variety of neoplasms, and is widely used in the clinical management of human malignancies including breast cancer.

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Potentiation of antitumor effect of CPA by AQ4N and tirapazamine on mammary carcinoma (Friery et al.,2000), and by bis-indole alkaloid on breast cancer cells has been reported (Leung et al., 2000). Very recently it has been demonstrated that coadministration of thalidomide and CPA
gave markedly greater activity against Colon 38 tumor compared with either drug alone (Ding et al., 2002).
Doxycycline (DOX), a commonly used antibiotic, has antitumor activity against several malignancies (Fife et al., 1998; Rubins et al., 2001). Recently it has been reported that DOX has potential treatment value in bone metastasis of breast cancer cells (Duivenvoorden et al., 2002). DOX
inhibits these effects by inhibiting matrix metalloproteinases (MMPs), not only in breast cancer cells but also in human endothelial, prostate cancer, osteocarcinoma cells of patients (Fife et al., 1997; Hanemaaijer et al., 1998). Moreover, it also inhibits cell proliferation and induces apoptosis in
various cancer cells (Rubins et al., 2001). All these studies demonstrate that this well-tolerated antibiotic may be effective in treatment of various human cancers, either alone or in combination therapy.
DOX is potentially beneficial in bone metastasis of breast cancer cells and CPA is an important component of chemotherapeutic regimen for treatment of breast cancers.
CPA, administered at 100 mg/kg/day ip dose in nude mice bearing tumor derived by injecting MCF-7 cells resulted in decreased tumor size by 50% compared to tumors in untreated animals (Fig. 1B). DOX injection alone did not significantly induce tumor regression. The co-administration of DOX (5 mg/kg/day) along with CPA further enhanced the tumor regression by more than 25% (Figs. 1B and C).
Therefore, it is clear that DOX, one of the better-absorbed antibiotics with longer half-life, can potentiate the antitumor activity of CPA in vivo.

Told by researcher that Doxycycline dosage in study below was too high for humans:

Anticancer Res. 2009 Oct;29(10):3995-4003.
Doxycycline induces apoptosis in PANC-1 pancreatic cancer cells.

Son K, Fujioka S, Iida T, Furukawa K, Fujita T, Yamada H, Chiao PJ, Yanaga K.
Department of Surgery, Jikei University Hospital, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. son@jikei.ac.jp
BACKGROUND: Tetracyclines such as doxycycline are reported to possess cytotoxic activity against mammalian tumor cells, but the mechanism of their effects on cell proliferation remains unclear. MATERIALS AND METHODS: The antitumor effect of doxycycline was investigated in human pancreatic cancer cell line, PANC-1. We also investigated the effect of doxycycline on expression of a potent proangiogenic factor, interleukin (IL)-8. RESULTS: In excess of 20 microg/ml, cytotoxic effects of doxycycline were accompanied by G(1)-S cell cycle arrest and DNA fragmentation in PANC-1 cells. Doxycycline consistently activated transcription of p53, p21 and Fas/FasL-cascade-related genes, while reducing the expression of Bcl-xL and Mcl-1. Doxycycline (5 microg/ml) below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. In the mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by 80%. CONCLUSION: These data suggest that doxycycline exerts its antitumor effect by activating proapoptotic genes, inhibiting IL-8 expression, and suppressing antiapoptotic genes.

PMID: 19846942 [PubMed - indexed for MEDLINE]

Suggesting why antibiotics and glucosamine have anticancer effects?

Curr Med Chem. 2009;16(29):3805-27.
Selective matrix metalloproteinase inhibitors for cancer.

Lia NG, Shib ZH, Tang YP, Duan JA.
Jiangsu Key Laboratory for TCM Formulae Research, Nanjing University of Chinese Medicine, 138 Xianlin Road, 210046, Nanjing, Jiangsu, P.R. China.
The matrix metalloproteinases are a family of nearly 30 enzymes that are intimately involved in tissue remodeling. Disease processes associated with the matrix metalloproteinases are generally related to imbalance between the inhibition and activation of matrix metalloproteinases resulting in excessive degradation of the extracellullar matrix. These include osteoarthritis, rheumatoid arthritis, tumor metastasis and congestive heart failure. Despite massive research and development efforts, there are only two drugs launched on the market: periostat (doxycycline), a tetracycline used for periodontal disease and glucosemine sulfate, for osteoarthritis. Possible reasons for the low success rate of matrix metalloproteinase inhibitors in the clinic are mainly from unwanted side effects caused by their lack of selectivity, since inhibition of collagenase-1 may be responsible for the musculoskeletal side effects observed clinically with broad-spectrum inhibitors. Considering these data, many efforts were directed to developing a more selective second generation of inhibitors against the specific matrix metalloproteinases believed to be involved in the different pathologies. This review mainly focuses on selective matrix metalloproteinase inhibitors development on matrix metalloproteinases in terms of antitumor since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, natural products and their derivatives. Through these methods, new hope is emerging in the form of synthetic and natural matrix metalloproteinase inhibitors for the prevention and treatment of cancer.

PMID: 19747139 [PubMed - indexed for MEDLINE]

Mol Cancer Ther. 2010 Jan 26. [Epub ahead of print]
Human Mutations That Confer Paclitaxel Resistance.

Yin S, Bhattacharya R, Cabral F.
Authors' Affiliation: Department of Integrative Biology and Pharmacology, and Graduate School of Biomedical Sciences, University of Texas Medical School, Houston, Texas.
The involvement of tubulin mutations as a cause of clinical drug resistance has been intensely debated in recent years. In the studies described here, we used transfection to test whether beta1-tubulin mutations and polymorphisms found in cancer patients are able to confer resistance to drugs that target microtubules. Three of four mutations (A185T, A248V, R306C, but not G437S) that we tested caused paclitaxel resistance, as indicated by the following observations: (a) essentially 100% of cells selected in paclitaxel contained transfected mutant tubulin; (b) paclitaxel resistance could be turned off using tetracycline to turn off transgene expression; (c) paclitaxel resistance increased as mutant tubulin production increased. All the paclitaxel resistance mutations disrupted microtubule assembly, conferred increased sensitivity to microtubule-disruptive drugs, and produced defects in mitosis. The results are consistent with a mechanism in which tubulin mutations alter microtubule stability in a way that counteracts drug action. These studies show that human tumor cells can acquire spontaneous mutations in beta1-tubulin that cause resistance to paclitaxel, and suggest that patients with some polymorphisms in beta1-tubulin may require higher drug concentrations for effective therapy. Mol Cancer Ther; 9(2); OF1-9.

PMID: 20103599 [PubMed - as supplied by publisher]