Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice

Yin, Weiwei; Zhang, Jing; Jiang, Yumin; Shen, Juan

doi:10.3892/etm.2014.1911

Cited by 14 publications

(12 citation statements)

References 22 publications

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“…Sections of tumor tissue were fixed in 10% neutral formalin buffer according to the standard procedure and then stained using an In Situ Cell Apoptosis Detection Kit IV following the manufacturer's instructions (Sigma-Aldrich, St. Louis, MO, USA) using conventional methods as described previously ( 26 ). The sections were analyzed under a confocal microscope (×200).…”

Section: Methodsmentioning

confidence: 99%

Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

Ren

Liu

Zhang

et al. 2016

Molecular Medicine Reports

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Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co-expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad-ING4-P53, cisplatin, or a combination of Ad-ING4-P53 and cisplatin (Ad-ING4-P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription-polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad-ING4-P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad-ING4-P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl-2 was decreased in the Ad-ING4-P53 + cisplatin group. This suggested that the enhanced cisplatin chemosensitivity with Ad-ING4-P53 gene therapy in hypopharyngeal cancer xenografts may be associated with apoptosis induction through upregulation of Bax expression and downregulation of Bcl-2. The results of the present study indicated that gene therapy combined with cisplatin treatment may be a promising treatment for human hypopharyngeal cancer.

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Section: Methodsmentioning

confidence: 99%

Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

Ren

Liu

Zhang

et al. 2016

Molecular Medicine Reports

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“…The results obtained coincide with the data presented in human medicine (Marchetti et al, 2008;Promzeleva et al, 2012) on the efficiency of using low molecular weight heparins against growths in the mammary gland in the postoperative period. In this case, the inhibition of the development and distribution of tumours is explained by the activation of apoptosis of neoplastic cells and inhibition of the expression of the vascular endothelial growth factor (Yin et al, 2014), by inflammation through NFkappaB, the main enzymes which negatively affect the matrix, platelet and adherence cell interaction, and the effect on the release of the tissue pathway inhibitor factor, inhibition of selective modulation (Mousa, 2010;Heyman & Yang, 2016).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological correction of the hemostasis system for the surgical treatment of bitches with tumours of the mammary gland

Bely

Rublenko

et al. 2018

Regul. Mech. Biosyst.

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We carried out the clinical validation of pathogenetically substantiated protocols for the treatment of female dogs with tumour lesions of the mammary gland. The positive effect of corrective therapy was characterized by a decrease in the physiological level of fibrinogen: in benign tumours in 10 days, malignant – in 14 days against the background of its stable high level in control animals with malignant neoplasia. In the postoperative period in experimental animals, the functioning of the internal coagulation unit was restored, as evidenced by the normalization of the activated partial thromboplastin time for benign tumours by days 10–14, malignant – by 14 days. In control patients, these changes were detected only for benign neoplasms. Shifts of the external mechanism of blood coagulation in the experimental groups were eliminated in benign neoplasia cases in 10 days, malignant cases in 14 days against the background of severe disorders in this link in control patients throughout the observation period. The positive effect of complex treatment regimens is confirmed by the restoration of total fibrinolytic activity by days 10–14 due to the normalization in the same terms of the plasminogen activator and tissue plasminogen activator by days 3–7. In control animals, the total fibrinolytic activity was consistent with those of clinically healthy animals only for benign neoplasms. The balancing of coagulation and fibrinolytic mechanisms was accompanied by a decrease in the activity of proteolytic inhibitors: α2-macroglobulin in experimental groups with benign neoplasia by day 10, malignant – by days 10–14, and control – respectively, by days 3 and 14; α1-proteinase inhibitor in all groups by day 3. Concentration of nitric oxide after extirpation of benign tumors already at day 3 of the postoperative period in all groups corresponded to the indexes of clinically healthy dogs, with the removal of malignant tumours – in experimental animals at day 3, control – at day 14. The content of malondialdehyde and ceruloplasmin against the background of pharmacological correction was restored by days 10–14, whereas in control animals – only with benign neoplasms by day 14. Postoperative pharmacological correction of the hemostasis system can significantly improve the results of treatment in cancer patients.

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“…This inhibition of metastases was probably dependent on the disruption of interactions between chemokines CXCR4 and CXCL12 [38]. In another animal experiment, LMWH administered together with adriamycin (antineoplastic agent) reduced the growth of breast cancer [39]. This anti-tumour effect was likely to be associated with the induction of apoptosis of cancerous cells and inhibition of angiogenesis within the tumour.…”

Section: Introductionmentioning

confidence: 96%

“…Rather, this attenuation of metastases is secondary to the restraint of P-and L-selectin-mediated interactions of the platelets with circulating neoplastic cells [16,43,[51][52][53][54][55], modulation of the chemokine CXCL12/CXCR4 axis [16,37,38,46,47,56,57], inhibition of heparanase activity [58][59][60][61], and inhibition of neoangiogenesis within the tumour (Figs. 2, 3, and 4) [39,40,50,[62][63][64][65]. LMWHs can also interfere with the activity of another class of adhesion molecules: integrins.…”

mentioning

confidence: 99%

Administration of low molecular weight heparins for prolonging the survival of patients with cancer

Majewski¹,

Simka²

2015

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Thromboembolism represents one of the most common causes of mortality and morbidity in cancer patients, and thromboembolic events occur more often in patients with biologically more aggressive malignant disease. Therefore, low molecular weight heparins (LMWHs) are routinely administered to cancer patients. Importantly, in addition to the prophylactic activity against thromboembolism, LMWHs seem to decrease mortality in these patients. Improved clinical prognosis is independent of the antithrombotic efficacy, since vitamin K antagonists do not improve patient survival, and non-anticoagulant heparins exhibit a similar anti-cancer effect. This protective effect is primarily related to the prevention of spreading of the cancer through metastases. The mechanisms responsible for heparin-dependent inhibition of metastases comprise: inhibition of integrins, restraint of P-and L-selectin-mediated interactions of the platelets with circulating neoplastic cells, silencing of the chemokine CXCL12/CXCR4 axis, inhibition of heparanase activity, inhibition of neoangiogenesis within the tumour, and reduced local generation of thrombin. A combined effect of the above-described mechanisms is also possible. Although at the moment cancer patients are not recommended routine administration of LMWHs for survival improvement, such a recommendation might be expected in the future. It is possible that for this purpose, instead of currently available agents, some novel heparins or similarly structured chemical compounds will be used. In the FAMOUS trial, carried out on a subgroup of patients with good clinical prognosis, administration of LMWH significantly improved their survival [17]. In the MALT study, administration of LMWH resulted in improved survival in cancer patients with advanced malignancy with a life expectancy of more than six months [29]. Similarly, cancer patients with good clinical prognosis benefited from LMWH administration in the CLOT study [19]. Also, a post-hoc analysis of the results of the PROTECHT study revealed improved survival, but only in patients responding to chemotherapy [30], while this beneficial effect was not seen in those not responding to the treatment [31]. On the other hand, such an anti-cancer protective effect was not found in other clinical trials assessing the survival benefit of LMWH administration. However, these trials examined patients with an advanced malignancy and poor clinical prognosis [32,33].Analysis of the above-mentioned trials suggests that in selected groups of cancer patients LMWHs improve survival irrespective of the antithrombotic efficacy of the drug, since vitamin K antagonists did not improve clinical prognosis [19]. Besides, this anti-cancer effect did not result from an inhibition of primary tumours, but rather from anti-metastatic activity [34,35]. Consequently, two published meta-analyses [36,37] suggest that LMWHs can improve the survival of cancer patients, primarily those with non-metastatic disease. It is also possible that at least some patients with advance...

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Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice

Cited by 14 publications

References 22 publications

Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

Pharmacological correction of the hemostasis system for the surgical treatment of bitches with tumours of the mammary gland

Administration of low molecular weight heparins for prolonging the survival of patients with cancer

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