The Impact of the Low Molecular Weight Heparin Tinzaparin on the Sensitization of Cisplatin-Resistant Ovarian Cancers—Preclinical In Vivo Evaluation in Xenograft Tumor Models

Abstract

Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. We have recently shown that LMWH reverses the cisplatin resistance of A2780cis human ovarian cancer cells in vitro. Here we address the question whether this LMWH effect is also valid under in vivo conditions. Therefore, we established tumor xenografts of A2780 and cisplatin resistant A2780cis cells in nude mice and investigated the impact of daily tinzaparin applications (10 mg/kg BW) on anti-tumor activity of cisplatin (6 mg/kg BW, weekly) considering the tumor growth kinetics. Intratumoral platinum accumulation was detected by GF-AAS. Xenografts of A2780 and A2780cis cells strongly differed in cisplatin sensitivity. As an overall consideration, tinzaparin co-treatment affected the response to cisplatin of A2780cis, but not A2780 tumors in the later experimental time range. A subgroup analysis confirmed that initially smaller A2780cis tumors benefit from tinzaparin, but also small A2780 xenografts. Tinzaparin did not affect cisplatin accumulation in A2780cis xenografts, but strongly increased the platinum content in A2780, obviously related to morphological differences in both xenografts. Although we cannot directly confirm a return of A2780cis cisplatin resistance by tinzaparin, as shown in vitro, the present findings give reason to discuss heparin effects on cytostatic drug efficiency for small tumors and warrants further investigation.

Non-Anticoagulant Heparins as Heparanase Inhibitors

“…Size fractionation of tinzaparin allowed separation of HMW fractions whose components, not present in the other two LMWHs, are endowed with high selectin inhibitory activity but low antiXa activity [74]. Preclinical in vivo evaluation in tumor xenografts models evidenced that tinzaparin was able to sensitize cis-platin resistant ovarian cancer [75]. A non-anticoagulant ultra LMWH (2.5 kDa), obtained by hydrogen peroxide catalyzed radical heparin hydrolysis assisted by ultrasonic waves, exhibited antiheparanase activity intermediate compared with those of tinzaparin (Mw 7 kDa), dalteparin (6.3 kDa) and enoxaparin (5.5 kDa) [76].…”

Selectins: An Important Family of Glycan-Binding Cell Adhesion Molecules in Ovarian Cancer

“…As an anticoagulant, low molecular weight heparin (LMWH) is recommended as the supporting antithrombotic therapy for patients with various types of cancer [ 85 , 86 ]. Administration of the LMWH tinzaparin can modulate drug sensitivity of platinum-resistant ovarian cancer xenografts and ovarian cancer cell lines [ 87 , 88 ]. There are reports that LMWHs helped in ovarian cancer patient survival during short-term administration, but did not significantly benefit patient survival after LMWH chronic administration.…”

“…There are reports that LMWHs helped in ovarian cancer patient survival during short-term administration, but did not significantly benefit patient survival after LMWH chronic administration. The inconsistent influence of LMWH on ovarian cancer in vitro and in vivo can be explained by the modulation of gene expression profile, which requires further studies [ 87 , 89 ]. Moreover, the abovementioned clinical trials involved patients with multiple histological cancer types.…”

Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas

“…Moreover, there have been numerous studies with experimental models such as cell lines, tissues, and mice in various types of cancers that have demonstrated the antitumor and antimetastatic effect LMWHs possess [12][13][14]. Furthermore, there have been clinical trials for small cell lung cancer (SCLC) and breast cancer where the overall survival of patients has been prolonged after the use of LMWHs [15][16][17].…”