Multi-Targeted Approach to Treatment of Cancer

Gandhi, Varsha; Mehta, Kapil; Grover, Rajesh K.; Pathak, Sen; Aggarwal, Bharat B.

doi:10.1007/978-3-319-12253-3

Cited by 2 publications

(2 citation statements)

References 648 publications

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“…Combination studies aim to reduce the amount of the drug needed to elicit a desired response, thereby, potentially reducing adverse side-effects, and overcoming resistance ( Ziauddin et al, 2014 ; AlFakeeh and Brezden-Masley, 2018 ; Luque-Bolivar et al, 2020 ). Generally, this multi-drug approach is used in cancer therapy to target alternative signalling pathways from those used by current SOC therapies in an attempt to delay resistance to the individual drugs ( Banerjee et al, 2008 ; Gandhi et al, 2015 ; Samadi et al, 2015 ). However, despite the fact that current SOC endocrine therapies mainly target the ER, the ER remains a viable target after the onset of resistance to SOC endocrine therapy ( Riggins et al, 2007 ; Rondón-Lagos et al, 2016 ; Luque-Bolivar et al, 2020 ; Yao et al, 2020 ), suggesting that the addition of another ER-targeted anti-cancer agent, such as SM6Met ( Visser et al, 2013 ; Oyenihi et al, 2018 ), in combination with current SOC endocrine therapies, like tamoxifen, could prove effective for overcoming breast tumour resistance to tamoxifen.…”

Section: Discussionmentioning

confidence: 99%

“…SM6Met, in the presence of E 2 , however, displayed similar cell cycle distribution patterns as a previous study also using MCF-7BUS ER + breast cancer cells ( Visser, 2013 ) by demonstrating arrest in the S phase. Thus, as 4-OH-Tam has been shown by others ( Osborne et al, 1983 , 1984 ; Lykkesfeldt et al, 1984 ; Yeh et al, 2014 ; Khamis et al, 2018 ) to arrest cells in the G0/G1 phase, while SM6Met arrests in the S phase, it implies that SM6Met may elicit its effects on the regulation of cell cycle machinery via a different mechanism to that of the SOC therapy, which is preferred for combination therapies as studies suggest breast cancer is more responsive to combinations that inhibit multiple molecular targets associated with the development and progression of breast cancer ( Gandhi et al, 2015 ; Samadi et al, 2015 ). Together this suggests that adding SM6Met to 4-OH-Tam mechanistically enhanced S phase arrest, which conceivably lead to morphological changes and a subsequent increase in apoptosis, thereby significantly enhancing the pro-apoptotic effects of 4-OH-Tam.…”

Section: Discussionmentioning

confidence: 99%

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Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells

2022

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Synergistic drug combinations are not only popular in antibiotic, anti-microbial, immune disease (i.e., AIDS) and viral infection studies, but has also gained traction in the field of cancer research as a multi-targeted approach. It has the potential to lower the doses needed of standard of care (SOC) therapeutic agents, whilst maintaining an effective therapeutic level. Lower dosages could ameliorate the fundamental problems such as drug resistance and metastasis associated with current SOC therapies. In the current study, we show that the combination of SM6Met with (2)-4-hydroxytamoxifen (4-OH-Tam, the active metabolite of tamoxifen) produces a strong synergistic effect in terms of inhibiting MCF7 ER-positive (ER+) breast cancer cell proliferation and that a 20 times lower dose of 4-OH-Tam in combination with SM6Met is required to produce the same inhibitory effect on cell proliferation as 4-OH-Tam on its own. Cell cycle analyses of the best combination ratios of SM6Met and 4-OH-Tam also suggests that the combination results in increased accumulation of cells in the S-phase and in the apoptotic phase. Moreover, the best combination ratio (20:1) of SM6Met with 4-OH-Tam displayed greater anti-metastatic potential in terms of inhibiting ER+ breast cancer cell migration, invasion, and colony formation than the SOC therapy alone, suggesting that SM6Met together with 4-OH-Tam could be a viable drug combination for not only delaying resistance and ameliorating the negative side-effects associated with current SOC therapies, like tamoxifen, but could also provide a novel, more affordable therapeutic alternative for treating or preventing ER+ breast cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells

2022

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Potent Anti-Ovarian Cancer with Inhibitor Activities on Both Topoisomerase II and V600EBRAF of Synthesized Substituted Estrone Candidates

et al. 2019

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A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol (3a–l) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives (4a–d) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2a,b which were treated with hydrazine derivatives in alcohols to give the corresponding derivatives 3a–l, respectively. Additionally, treatment of 2a,b with methyl- or phenylhydrazine in ethanolic potassium hydroxide afforded the corresponding N-substituted pyrazoline derivatives 4a–d, respectively. All these derivatives showed potent anti-ovarian cancer both in vitro and in vivo. The mechanism of anti-ovarian cancer was suggested to process via topoisomerase II and V600EBRAF inhibition.

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Multi-Targeted Approach to Treatment of Cancer

Cited by 2 publications

References 648 publications

Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells

Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells

Potent Anti-Ovarian Cancer with Inhibitor Activities on Both Topoisomerase II and V600EBRAF of Synthesized Substituted Estrone Candidates

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