Breast cancer (BC) is a global problem accounting for 11.7% of all cancers, with a 5-year prevalence of 15.4% (Sung et al., 2021). In the 1980s, it was believed that BC was a localized and regionally advanced disease. Hence, aggressive radical surgery was routinely practiced to prevent any relapse (Cotlar et al., 2003). However, the failure of radical surgery to contain relapse and distant recurrence, which in turn led to increased mortality rates, perhaps became the turning point toward new approaches involving less aggressive sublime surgery and adjuvant chemotherapy (AC) (Anampa et al., 2015). Currently, adjuvant chemotherapy for BC patients is a widely used regimen for treating tumors due to its potential to increase overall survival (OS) and disease-free survival (DFS) rates. It has been reported that first-generation AC drugs are associated with a 35% reduction in mortality, second-generation AC drugs are associated with a 20% reduction in mortality compared with first-generation AC drugs, and third-generation AC drugs are associated with a 20% reduction in mortality compared with second-generation AC drugs (Anampa et al., 2015). There have been some concerns about the use of adjuvant therapies in breast cancer, mainly due to a) the short follow up of these types of therapies compared to the earlier standard regimens, b) although very effective, the magnitude of the benefit is small and c) most trials have a small number of elderly patients in the study, hence whether this therapy can be extrapolated to elderly patients (>65 years of age) who account for almost 50% of the breast cancer patients (Montemurro et al., 2005). Despite all these, however, there is little controversy over the existence of benefits reaped by a large proportion of breast cancer patients (Montemurro et al., 2005). The benefits of adjuvant chemotherapy are limited in TNBCs with <0.5 cm, while TNBCs with 0.5–1.0 cm are a grey area; whereas, the benefits of adjuvant chemotherapy are visible in the TNBC >1.0 cm groups (Marra and Curigliano, 2021). Even with these advancements in AC treatment, major tumor cell characteristics, such as metastasis, invasive phenotype, epithelial mesenchymal transition (EMT) and cancer stem cell progression, escape from immunosurveillance and drug treatments and thus remain major obstacles in cancer therapy.

Paclitaxel (PTX), a phytocompound extracted from the bark of Taxus brevifolia (Pacific yew), is known to bind to microtubules, thereby inhibiting depolymerization and stabilizing the microtubules (Weaver, 2014). Furthermore, it causes abnormal chromosomal segregation and mitotic arrest in cells (Bachegowda et al., 2014; Weaver, 2014). PTX is regarded as an effective cytotoxic agent and is widely used to treat both early and metastatic BC. However, when used alone, PTX has a low pathologic complete response (pCR) rate. This rate increases 8–31% when combined with other drugs, such as cyclophosphamide, doxorubicin, docetaxel, 5-fluorouracil, methotrexate or vinorelbine (Bachegowda et al., 2014). On the other hand, the combination of PTX with radiation therapy has invariably led to extreme undesirable toxic side effects in patients (Burris and Hurtig, 2010). Despite PTX being effective in the management of breast cancer, its side effects are of grave concern.

Efforts are being made to mitigate the side effects of chemotherapeutic drugs (such as PTX) without affecting their efficacy and sensitivity using adjuvants. The adjuvants of plant origin could be novel entities, modified drugs or combinations of extracts/phytocompounds given together with the existing drug or in stepwise succession (Choudhari et al., 2020; Ho and Cheung, 2015; Hosein Farzaei et al., 2016; Liu et al., 2021; Rizeq et al., 2020). Ayurveda encompasses a well-known Indian traditional medicinal system and uses multiple herbs as well as their products in the form of formulations to treat various ailments and influence the health of individuals. Asparagus racemosus Willd. (AR; Ayurvedic name: Shatavari) and Withania somnifera (L.) Dunal (WS; Ayurvedic name: Ashwagandha) are among the plants widely used to treat various diseases, including cancer (Mehta et al., 2021; Mitra et al., 2012; Rai et al., 2016; Singh et al., 2021; Widodo et al., 2007).

AR has been reported to possess adaptogenic (Rege et al., 1999; Singh and Geetanjali, 2016), antibacterial (Mandal et al., 2000), antioxidant (Selvaraj et al., 2019; Singh and Geetanjali, 2016), antidiabetic (Vadivelan et al., 2019), antiulcer (Singh and Geetanjali, 2016), immunoadjuvant (Alok et al., 2013), phytoestrogenic (Singh and Geetanjali, 2016) and radioprotective properties (Kamat et al., 2000). AR also showed anticancer effects in Ehrlich ascites carcinoma-bearing mice (Mitra et al., 2012) and in T47D human BC cell lines. AR root extracts inhibited hepatocarcinogenesis in Wistar rats (Agrawal et al., 2008). A recent in vivo study showed recovery from the myelosuppressive effects of PTX by AR in mouse models (Saggam et al., 2022). A study on mice also reported that a lectin from AR roots inhibited 68% of Ehrlich ascites carcinomas after treatment for 5 days (Kabir et al., 2021). However, detailed studies on the underlying mechanisms and effects of AR on EMT and in vivo animal studies of AR with respect to BC remain to be reported.

WS is widely known for its anticancer properties (Dar et al., 2015; Rai et al., 2016; Singh et al., 2021). Withaferin A, a phytocompound of WS, showed promising antitumor synergism in combination with sorafenib in thyroid cancer (Cohen et al., 2012), with cisplatin in ovarian cancer (Kakar et al., 2014) and with oxaliplatin in pancreatic cancer (Li et al., 2015). Although WS root extracts have been shown to possess antitumor activities with various mechanisms of action, including the inhibition of EMT (Lee et al., 2015; Yang et al., 2013), the effect of WS in combination with PTX on tumor cell sensitivity and drug efficacy has not been reported.

The present investigation focused on understanding the complementary effects of two traditional plant extracts, AR and WS, in combination with PTX on BC in vitro as well as in a xenograft mouse model. We report a) the effects of WS and AR root extracts on human BC cells, b) novel mechanisms of action involving the induction of senescence and EMT inhibition by AR and c) their effects in combination with PTX in mouse tumor models in vivo. This study also highlights the potential use of WS and AR as response modifiers for chemotherapy in the treatment of breast cancer.