Abstract:Abstract. Combined therapy with multiple drugs is a common practice in the treatment of cancer, which can achieve better therapeutic effects than a single drug, and can reduce the side effects as well as drug resistance. This study aimed to determine whether aspirin (ASA) shows synergism with doxorubicin (DOX) in HepG2 human hepatocellular carcinoma cells in vitro and in a HepG2 cell xenograft model in BALB/c nude mice. When treated in combination, DOX (0.25 nmol/ ml) and ASA (5 µmol/ml) produced strong synerg… Show more
“…While not statistically significant, the treatment of tumors derived from A549 cells with doxorubicin resulted in a small effect (Cohen’s d = 0.51 [−0.62, 1.63]), which is in the expected direction. A small reduction in tumor weight compared to vehicle control has also been reported in other studies that utilized a similar low dose doxorubicin experimental design (Biswas et al, 2013; Hossain et al, 2012; Lopez et al, 2009; Wang et al, 2010). 10.7554/eLife.17044.004Figure 2.Final tumor weights from xenograft experiment testing efficacy of cimetidine in inhibiting the growth of tumors in SCID mice.At the end of the predefined study period (Day 12), tumors from the xenograft experiment reported in Figure 1 were excised and weighed.…”
Section: Resultssupporting
confidence: 74%
“…Additionally, mice treated with doxorubicin started to lose weight and had a rough coat starting on approximately day 7 of the treatment schedule. A small reduction in tumor volume compared to vehicle control has also been reported in other studies that utilized low dose doxorubicin experimental designs (Hossain et al, 2012; Lopez et al, 2009; Wang et al, 2013, 2010). …”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data“ (Sirota et al., 2011). Here we report the results of those experiments. We found that cimetidine treatment in a xenograft model using A549 lung adenocarcinoma cells resulted in decreased tumor volume compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 4C; Sirota et al., 2011), it was not statistically significant. Cimetidine treatment in a xenograft model using ACHN renal cell carcinoma cells did not differ from vehicle control treatment, similar to the original study (Supplemental Figure 1; Sirota et al., 2011). Doxorubicin treatment in a xenograft model using A549 lung adenocarcinoma cells did not result in a statistically significant difference compared to vehicle control despite tumor volume being reduced to levels similar to those reported in the original study (Figure 4C; Sirota et al., 2011). Finally, we report a random effects meta-analysis for each result. These meta-analyses show that the inhibition of A549 derived tumors by cimetidine resulted in a statistically significant effect, as did the inhibition of A549 derived tumors by doxorubicin. The effect of cimetidine on ACHN derived tumors was not statistically significant, as predicted.DOI:
http://dx.doi.org/10.7554/eLife.17044.001
“…While not statistically significant, the treatment of tumors derived from A549 cells with doxorubicin resulted in a small effect (Cohen’s d = 0.51 [−0.62, 1.63]), which is in the expected direction. A small reduction in tumor weight compared to vehicle control has also been reported in other studies that utilized a similar low dose doxorubicin experimental design (Biswas et al, 2013; Hossain et al, 2012; Lopez et al, 2009; Wang et al, 2010). 10.7554/eLife.17044.004Figure 2.Final tumor weights from xenograft experiment testing efficacy of cimetidine in inhibiting the growth of tumors in SCID mice.At the end of the predefined study period (Day 12), tumors from the xenograft experiment reported in Figure 1 were excised and weighed.…”
Section: Resultssupporting
confidence: 74%
“…Additionally, mice treated with doxorubicin started to lose weight and had a rough coat starting on approximately day 7 of the treatment schedule. A small reduction in tumor volume compared to vehicle control has also been reported in other studies that utilized low dose doxorubicin experimental designs (Hossain et al, 2012; Lopez et al, 2009; Wang et al, 2013, 2010). …”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Discovery and Preclinical Validation of Drug Indications Using Compendia of Public Gene Expression Data“ (Sirota et al., 2011). Here we report the results of those experiments. We found that cimetidine treatment in a xenograft model using A549 lung adenocarcinoma cells resulted in decreased tumor volume compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 4C; Sirota et al., 2011), it was not statistically significant. Cimetidine treatment in a xenograft model using ACHN renal cell carcinoma cells did not differ from vehicle control treatment, similar to the original study (Supplemental Figure 1; Sirota et al., 2011). Doxorubicin treatment in a xenograft model using A549 lung adenocarcinoma cells did not result in a statistically significant difference compared to vehicle control despite tumor volume being reduced to levels similar to those reported in the original study (Figure 4C; Sirota et al., 2011). Finally, we report a random effects meta-analysis for each result. These meta-analyses show that the inhibition of A549 derived tumors by cimetidine resulted in a statistically significant effect, as did the inhibition of A549 derived tumors by doxorubicin. The effect of cimetidine on ACHN derived tumors was not statistically significant, as predicted.DOI:
http://dx.doi.org/10.7554/eLife.17044.001
“…The planned pairwise comparison of TUNEL staining in tumors from mice treated with DOX + PBS compared to DOX + iRGD was also not statistically significant ( t (15) = 0.435, p =0.670, a priori significance threshold = 0.05). Other studies that utilized a similarly low dose of doxorubicin to reduce side effects, also reported small reductions in tumor weight compared to vehicle control with minimal and not statistically significant changes in TUNEL staining (Hossain et al, 2012; Sugahara et al, 2015; Wang et al, 2010). 10.7554/eLife.17584.007Figure 4.TUNEL staining of mouse tissues.Mice bearing orthotopic 22Rv1 human prostate tumors were intravenously injected with PBS alone (PBS), 1 mg/kg DOX and PBS (DOX + PBS), or 1 mg/kg DOX and 4 µmol/kg of iRGD (DOX + iRGD).…”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs“ (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result.DOI:
http://dx.doi.org/10.7554/eLife.17584.001
“…In combination, aspirin and doxorubicin resulted in enhanced effects in inhibiting tumor growth, arresting cell cycle and causing apoptosis in vitro when compared to single treatments. Combination therapy also resulted in synergistic antitumor activity in the xenograft model in nude mice 63. Others have shown that varied concentrations of aspirin,64 metformin,65 and heparin66 have shown efficacy in treating cancer when given in conjunction with chemotherapy.…”
Section: Combination Therapy: Targeted Multimodality Approach To Breamentioning
One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation.
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